Gastric retentive dosage forms for extended release of acamprosate into the upper gastrointestinal tract

ABSTRACT

Gastric retentive dosage forms for sustained release of acamprosate are described which may allow once- or twice-daily dosing for both acute and long-term treatment of a disorder including alcohol dependence, tinnitus, sleep apnea, Parkinson&#39;s disease, levodopa-induced dyskinesias in Parkinson&#39;s disease, Alzheimer&#39;s disease, Huntington&#39;s disease, Amyotrophic lateral sclerosis, Cortical spreading depression, migraine, schizophrenia, anxiety, tardive dyskinesia, spasticity, multiple sclerosis, various types pain, or binge eating. Methods of treatment using the dosage forms and methods of making the dosage forms are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.13/247,956, filed on Sep. 28, 2011, now allowed, which claims thebenefit of U.S. Provisional Application No. 61/387,368, filed Sep. 28,2010, the contents of which are incorporated herein by reference intheir entirety.

TECHNICAL FIELD

The present subject matter relates generally to dosage forms forextended release of acamprosate into the stomach of a patient in the fedmode and to methods of treatment using the dosage forms.

BACKGROUND

Acamprosate (calcium bis acetyl-homotaurine), is a synthetic analog ofγ-amino butyric acid (GABA) and is used as an adjunct for treatment ofalcohol dependence. Alcohol dependence is a chronic relapsing medicaldisorder which bears many of the characteristics of other medicalrelapsing disorders such as diabetes and hypertension. Withoutpharmacological treatment to accompany psychotherapy, up to 70% ofpatients resume drinking within one year (see Bankole et al., BiochemPharmacol., 2008, 75:34-56).

As alcohol inhibits the activity of N-methyl-D-aspartate receptors(NMDARs), chronic alcohol consumption leads to the upregulation of thesereceptors. Sudden alcohol abstinence results in excessive activation ofNMDARs, leading to symptoms such as delirium tremens and excitotoxicneuronal death (Tsai et al., Ann Rev Med, 1998, 155:726-732; Tsai etal., Am J Psych, 1998, 155:726-732). Acamprosate reduces this effect invivo. Studies have also suggested that acamprosate protects culturedcells in excitotoxicity induced by ethanol withdrawal, and by glutamateexposure combined with ethanol withdrawal.

Absorption of acamprosate following oral administration occurs via bothpassive diffusion through the intestinal epithelium and active uptakevia amino acid transporter that are expressed in the small intestine(Mas-Serrano et al., Alcohol & Alcoholism, 2000, 35:324-330).Acamprosate exhibits poor absorption in the intestine after oral dosing.It is thought this is primarily due to poor permeability in theintestinal epithelium. Moreover, the uptake transporter in the smallintestine becomes saturated with the current dosage form at the dose of2×333 mg, equivalent to 600 mg of acamprosate free acid, three timesdaily. Poor absorption not only reduces therapeutic effectiveness of anacamprosate oral dosage form, but also unabsorbed drug passes to thelower GI, resulting in adverse side effects such as diarrhea. Some ofthese and other side effects are related to the large amounts ofcalcium, and replacement or elimination of calcium with other cations,e.g., magnesium or sodium, may be beneficial.

Accordingly, it would be useful to manufacture an oral dosage form whichis able to provide prolonged and steady levels of acamprosate to thesmall intestine at concentrations which allow optimal uptake by theintestinal transporter and an effectively longer time for intestinalabsorption.

Gastric retained forms that can form the basis for the sustained releaseof a drug have been previously described, for example, in Gusler et al.(U.S. Pat. No. 6,723,340), Berner et al. (U.S. Pat. No. 6,488,962),Shell et al., (U.S. Pat. No. 6,340,475) and Shell et al. (U.S. Pat. No.6,635,280). These formulations make use of one or more hydrophilicpolymers which swell upon intake of water from gastric fluid. Thus, whenadministered in the fed mode, when the diameter of the pyloric sphincteris contracted and reduced, the dosage form will swell to a size to beretained in the stomach for a minimum of four hours or more. Theseformulations may be designed to produce desired release and deliveryprofiles for both highly soluble and poorly soluble drugs.

As presently disclosed, gastric retentive dosage forms are formulatedspecifically to provide extended release of acamprosate or of a salt orprodrug of acetyl homotaurine from the stomach into the uppergastrointestinal tract, resulting in prolonged exposure and lower butsteady release rate of the acamprosate or related salt or prodrug to thesmall intestine to optimize uptake and enhance bioavailability. Thesegastric retentive dosage forms are proposed to be administered with ameal. Gastric retentive dosage forms are generally applicable to drugswhere the bioavailability improves when administered with a meal. Sincethe AUC and Cmax of the current acamprosate dosage form decrease by 23%and 42%, respectively, when administered with food instead of fasting,it is surprising that acamprosate can be administered with goodbioavailability from a gastric retentive dosage form that depends onadministration in the fed mode.

BRIEF SUMMARY

The present disclosure provides, among other aspects, gastric retentivedosage forms for oral administration to a subject, such as a humanpatient, for the treatment of alcohol dependence, tinnitus, sleep apnea,levodopa-induced dyskinesias in Parkinson's disease, Alzheimer'sdisease, Huntington's disease, amyotrophic lateral sclerosis, corticalspreading depression, migraine, schizophrenia, anxiety disorders, motiondisorders, tardive dyskinesia, spasticity, multiple sclerosis, varioustypes pain, or binge eating. The dosage form in some embodiments is agastric retentive dosage form that contains a dose of acamprosate in anextended release (“ER”) formulation.

In a first aspect, a gastric retained extended release (ER) oral dosageform comprising a dose of acamprosate dispersed in a polymer matrixcomprising at least one hydrophilic polymer is provided. Uponadministration, the polymer matrix swells upon imbibition of fluid to asize sufficient such that the dosage form is retained in the stomach ofa subject in a fed mode and the dose of acamprosate is released over anextended period of time.

In one embodiment, the acamprosate is acamprosate calcium. In anotherembodiment, the acamprosate is in a free acid form. In still anotherembodiment, another pharmaceutically acceptable salt of acamprosate isused, including magnesium, sodium or potassium.

In one embodiment, the gastric retained ER dosage form provides a meanAUC of plasma acamprosate in the subject which is greater than the meanAUC of plasma acamprosate provided by an immediate release (IR)acamprosate dosage form, wherein the dose of acamprosate in the ERdosage form is the same as or less than the dose in the IR dosage form.In another embodiment, the mean AUC of plasma acamprosate is about 10%to 50%, about 15% to about 30%, about 5% to 15%, about 5% to 20%, about10% to 20%, about 10% to 25%, about 15% to 25%, about 20% to 25%, about20% to 30%, about 20% to 40%, or about 30% to 40% greater than the AUCof plasma acamprosate provided by administration of the IR dosage formto the subject. In another embodiment, the mean AUC of plasmaacamprosate is about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% ormore than about 50% greater than the mean AUC of plasma acamprosateprovided by administration of the IR dosage form to the subject.

In one embodiment, the gastric retained ER dosage form provides a meanCmax of plasma acamprosate in the subject which is less than the meanCmax of plasma acamprosate provided by an immediate release (IR)acamprosate dosage form, wherein the dose of acamprosate in the ERdosage form is the same as the dose in the IR dosage form. In anotherembodiment, the mean Cmax of plasma acamprosate is about 10% to 50%,about 15% to about 30%, about 5% to 15%, about 5% to 20%, about 10% to20%, about 10% to 25%, about 15% to 25%, about 20% to 25%, about 20% to30%, about 20% to 40%, or about 30% to 40% less than the Cmax of plasmaacamprosate provided by administration of the IR dosage form to thesubject. In another embodiment, the mean Cmax of plasma acamprosate isabout 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more than about50% less than the mean Cmax of plasma acamprosate provided byadministration of the IR dosage form to the subject.

In one embodiment, the gastric retained ER dosage form provides a meanTmax for plasma acamprosate in the subject who has been administeredacamprosate in the ER dosage form as described herein is greater thanthe mean Tmax of plasma acamprosate provided by an immediate release(IR) acamprosate dosage form, wherein the dose of acamprosate in the ERdosage form is the same as the dose in the IR dosage form. In anotherembodiment, the mean Tmax for plasma acamprosate in the subject who hasbeen administered acamprosate in the ER dosage form as described hereinis about 2 hours (h) to 5 h, about 3 h to 5 h, about 4 h to 5 h, about 2h to 6 h, about 3 h to 6 h, about 3 h to 5 h, about 3 h to 4 h, or about4 h to 6 h.

In one embodiment, the oral dosage form is a tablet. In anotherembodiment, the total tablet weight is about 500 mg or about 1000 mg(milligrams). In still another embodiment, the total tablet weight isabout 1200 mg. In yet another embodiment, the total tablet weight isabout 500 mg to about 1500 mg, 750 mg to 1500 mg, 800 mg to 1300 mg, 900mg to 1250 mg, or about 800 to 1200 mg.

In one embodiment, the tablet comprises a total of about 200 mg to about1000 mg, or about 300 mg to about 750 mg acamprosate. In anotherembodiment, the tablet comprises about 300 mg to 850 mg, 350 mg to 800mg, 400 mg to 700 mg, 450 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg,800 mg, or 850 mg acamprosate. In yet another embodiment, the tabletcomprises about 50 wt % (weight percent) or about 75 wt % acamprosate.In still another embodiment, the tablet comprises about 30 wt %, 35 wt%, 40 wt %, 45 wt %, 55 wt %, 60 wt %, 65 wt %, 70 wt %, 75 wt % orabout 80 wt % acamprosate.

In one embodiment, the tablet comprises about 20 mg, 25 mg, 30 mg, 35mg, 40 mg, 45 mg, or 50 mg of one or more binders. In anotherembodiment, the tablet comprises about 1 wt %, 2 wt %, 2.5 wt %, 3 wt %,3.5 wt %, 4 wt %, 4.5 wt %, 5 wt %, or 6 wt % binder. In yet anotherembodiment, the tablet comprises about 1 wt % to about 6 wt % or about 2wt % to about 5 wt % of a binder.

In one embodiment, the tablet comprises a binder which ispolyvinylpyrrolidone, polyvinylalcohol, ethyl cellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose,hydroxyethylcellulose or polyethylene glycol. In yet another embodiment,the polyvinylpyrrolidone is povidone, copovidone. In yet anotherembodiment, the tablet comprises a combination of more than one binder.

In one embodiment, the tablet comprises about 380 mg, 400 mg, 420 mg,440 mg, 460 gm, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg,or 620 mg of one or more hydrophilic polymers. In another embodiment,the tablet comprises about 15 wt % to about 50 wt %, about 20 wt % toabout 75 wt %, about 25 wt % to about 60 wt %, about 30 wt % to about 45wt %, about 25 wt % to about 40 wt %, or about 30 wt % to about 50 wt %of a hydrophilic polymer. In yet another embodiment, the tabletcomprises about 15 wt %, 18 wt %, 20 wt %, 25 wt %, 28 wt %, 30 wt %, 32wt %, 33 wt %, 35 wt %, 37 wt %, 40 wt %, 45 wt %, 50 wt %, 55 wt %, 60wt %, 65 wt %, 70 wt %, 75 wt %, 80 wt %, 85 wt %, or 90 wt % of ahydrophilic polymer.

In one embodiment, the tablet comprises one or more hydrophilicpolymers, each having an average molecular weight ranging from about200,000 Da (Daltons) to about 10,000,000 Da, about 900,000 Da to about5,000,000 Da, about 2,000,000 Da to about 5,000,000 Da, from about4,000,000 Da to about 5,000,000 Da, from about 5,000,000 Da to about7,000,000 Da, from about 2,000,000 Da to about 4,000,000 Da, from about900,000 Da to about 5,000,000 Da, or from about 900,000 Da to about4,000,000 Da. In another embodiment, the tablet comprises a hydrophilicpolymer having an average molecular weight of about 200,000 Da, 600,000Da, 900,000 Da, 1,000,000 Da, 2,000,000 Da, 4,000,000 Da, 5,000,000 Da,7,000,000 Da, 10,000,000 Da or 12,000,000 Da. In still anotherembodiment, the hydrophillic polymer has a viscosity range from about 55cp to 17,600 cp in a 5% solution at 25° C., from about 400 cp to 4,000cp in a 2% solution at 25° C. or from about 1,650 cp to 10,000 cp in a1% solution at 25° C.

In one embodiment, the ER layer comprises a hydrophilic polymer which isa cellulose-based or cellulose-derived polymer having an averageviscosity ranging from about 4,000 cp (centipoise) to about 200,000 cp,from about 50,000 cp to about 200,000 cp, or from about 80,000 cp toabout 120,000 cp as measured as a 2% weight per volume in water at 20°C.

In one embodiment, the ER layer comprises a hydrophilic polymer which isa cross-linked polyacrylic acid. In another embodiment, the polyacrylicacid has a viscosity range from about 4 to 40,000 cp for a 1% solutionat 25° C.

In one embodiment, the one or more hydrophilic polymers in the tablet isa polyalkylene oxide. In another embodiment, the hydrophilic polymer ispoly(ethylene oxide). In yet another embodiment, the at least onehydrophilic polymer in the tablet is a cellulose. In yet anotherembodiment, the cellulose is hydroxypropyl methylcellulose.

In one embodiment, the tablet comprises two hydrophilic polymers in aratio of 1:1, 1.2:1, 1.3:1, 1, 4:1, 1.5:1, 1.6:1, 1.8:1, or 2.0:1.

In one embodiment, the tablet comprises about 8 mg, 9 mg, 10 mg, 11 mg,12 mg, 13 mg, 14 mg, or 15 mg of one or more lubricants. In anotherembodiment, the tablet comprises about 0.5 wt % to about 2.5 wt % of alubricant. In yet another embodiment, the tablet comprises about 0.5 wt%, 1.0 wt %, 1.5 wt %, 2.0 wt %, or 2.5 wt % of a lubricant.

In one embodiment, the tablet comprises a lubricant which is magnesiumstearate, calcium stearate, sodium stearyl fumarate, stearic acid,stearyl behenate, glyceryl behenate, or polyethylene glycol.

In one embodiment, the tablet comprises one or more additionalexcipients which are diluents, coloring agents, flavoring agents, and/orglidants.

In one embodiment, the dosage form is a single layer tablet. In anotherembodiment, the dosage form comprises a coat. In yet another embodiment,the coat comprises one or more active agents. In still anotherembodiment, the coat comprises the acamprosate.

In one embodiment, the dosage form comprises a coat which does notfunction as an enteric coating.

In one embodiment, the dosage form is a tablet which comprises entericcoated particles of acamprosate. In another embodiment, the enteric coatdissolves at a pH of less than about 7.0, 6.5, 6.0, 5.5 or 5.0. In stillanother embodiment, the enteric coat dissolves at a pH of about 5 to 6,or about 5.5 to 6.5.

In one embodiment, the dosage form is a bilayer or multilayer tablet. Inanother embodiment, the dosage form comprises a layer which is afloating layer. In still another embodiment, the dosage form comprises alayer which is an IR layer.

In one embodiment, the dosage form is an osmotic dosage form.

In one embodiment, the dosage form comprises an immediate release matrixcontaining the acamprosate, surrounded by a rate-limiting membrane. Inanother embodiment, the rate-limiting membrane functions as asemi-permeable membrane when immersed in fluid.

In one embodiment, the dosage form comprises a second therapeutic agent.In another embodiment, the second therapeutic agent is naltrexone. Inyet another embodiment, the second therapeutic agent is formulated forextended release or immediate release.

In one embodiment, the dosage form is formulated to provide sustainedrelease of the acamprosate and the second therapeutic agent.

In one embodiment, the single layer, bilayer, multilayer tablet has afriability of no greater than about 0.1%, 0.2% 0.3%, 0.4%, 0.5%, 0.7% or1.0%.

In one embodiment, the tablet has a hardness of at least about 10kiloponds (kp). In some embodiments, the tablet has a hardness of about9 kp to about 25 kp, or about 12 kp to about 20 kp. In furtherembodiments, the tablet has a hardness of about 11 kp, 12 kp, 13 kp, 14kp, 15 kp, 16 kp, 17 kp, 18 kp, 19 kp, 20 kp, 21 kp, 22 kp, 23 kp, 24 kpor 25 kp.

In one embodiment, the tablets have a content uniformity of from about85 to about 115 percent by weight or from about 90 to about 110 percentby weight, or from about 95 to about 105 percent by weight. In otherembodiments, the content uniformity has a relative standard deviation(RSD) equal to or less than about 3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1.0% or0.5%.

In one embodiment, at least 80% of the acamprosate is released from thetablet over a time period of about 5 to 13 h (hours), about 6 to 12 h,about 7 to 10 h, about 8 to 9 h, about 6 h to 9 h, about 8 to 10 h, orabout 9 to 10 h. In another embodiment, the acamprosate is delivered tothe small intestine of a subject over a time period of at least about 4h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, or 13 h.

In one embodiment, the acamprosate is in enteric coated particles orbeads. In another embodiment, the acamprosate is released from thetablet via erosion. In another embodiment, the acamprosate, especiallyif it is not in enteric coated particles, is released from the tabletvia diffusion. In yet another embodiment, the acamprosate is releasedfrom the tablet via a combination of erosion and diffusion.

In one embodiment, about 5% to about 20% of the dose of acamprosate inthe ER portion of the dosage form is released within 10 minutes, 15minutes, 30 minutes, 45 minutes or 60 minutes after oral administration.

In one embodiment, not more than about 15%, 20%, 30%, or 40% of the doseof acamprosate is released within about the first hour. In anotherembodiment, not more than about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%,65%, 70%, 75%, or 80% of the dose of acamprosate is released withinabout 4 hours.

In one embodiment, at least about 80% of the acamprosate in the ERportion of the dosage form is released from the dosage form after about6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours or 12 hours ofadministration.

In one embodiment, the tablet swells upon imbibition of fluid fromgastric fluid to a size which is approximately 15%, 20%, 25%, 30%, 35%40%, 45%, or 50% larger than the size of the tablet prior to imbibitionof fluid. In other embodiments the tablet swells to a size that is 75%,100%, 200%, 300% or even greater than the original size of the tablet.

In one embodiment, the dosage form provides a dissolution profilewherein between about 50% to about 85%, about 55% to about 80% or about35% to about 55% of the dose of acamprosate remains in the tabletbetween about 1 and 2 hours after administration. In yet anotherembodiment, not less than about 50%, 55%, 60%, 65%, 70%, or 75% isreleased after about 6 hours. In yet another embodiment, not less thanabout 60% is released after about 6 hours.

In a second aspect, a method of making a gastric retentive dosage formcomprising acamprosate and at least one hydrophilic polymer is provided.In one embodiment, the acamprosate is acamprosate calcium.

In one embodiment, a method of making the dosage form comprising wetgranulating acamprosate with one or more binders and/or one or moredisintegrants is provided, wherein granules are formed. In anotherembodiment, the method of making the dosage form further comprisesscreening the dry granules based on size. In yet another embodiment, themethod of making the dosage form further comprises blending the granuleswith additional excipients.

In one embodiment, a gastric retained dosage form comprising acamprosateand at least one swellable polymer is administered to a subjectsuffering from or diagnosed with alcohol dependence.

In one embodiment, a gastric retained dosage form comprising acamprosateis administered to a subject in a fed mode. In another embodiment, thedosage form is administered with a meal to a subject once in a 24 hourperiod. Dinner may be the preferred meal. In other embodiments, thedosage form is administered with a meal to the subject twice or thricein a 24 hour period. Breakfast and dinner may be the preferred meals forthe twice daily dose. The dosage administered with the evening meal mayor may not be greater than with the morning meal. In yet anotherembodiment, the dosage form is administered with a meal to a subjectonce or twice in a 24 hour period for 2, 3, 4, 5, 6, 7, 8 or more days.

In one aspect, a method of treatment comprises administering to asubject in need thereof a dose of acamprosate or a pharmaceuticallyacceptable salt thereof dispersed in a polymeric matrix wherein thepolymeric matrix comprises one or more polymers that upon imbibition offluid swells to a size sufficient to promote gastric retention, whereinupon administration to the subject, the gastric retentive dosage formprovides a mean AUC of plasma acamprosate greater than the mean AUC ofplasma acamprosate provided by an immediate release (IR) dosage formwhich contains a dose of acamprosate or pharmaceutically acceptable saltthereof equal to or more than the dose of acamprosate in the gastricretentive dosage form.

In one embodiment, the subject is administered a total daily dose ofabout 300 mg to about 2500 mg acamprosate. In another embodiment, thetotal daily dose is about 300 mg to about 2000 mg, about 500 mg to about1500 mg, about 600 mg to about 1200 mg, or about 300 mg, 400 mg, 500 mg,600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1500 mg, 1600mg, 1800 mg, 2000 mg, 2200 mg, or 2500 mg.

In one embodiment, the total daily dose is administered via aonce-per-day regimen or via a twice-per-day regimen.

In a third aspect, a method for treating a subject suffering fromalcohol dependence, tinnitus, sleep apnea, Parkinson's disease,levodopa-induced dyskinesias in Parkinson's disease, Alzheimer'sdisease, Huntington's disease, Amyotrophic lateral sclerosis, Corticalspreading depression, migraine, schizophrenia, anxiety, tardivedyskinesia, spasticity, multiple sclerosis, various types pain, or bingeeating, comprising administering a gastric retained acamprosate oraldosage form is provided.

In one embodiment, the acamprosate is a free acid, acamprosate calcium,or another pharmaceutically acceptable salt of acamprosate.

In one embodiment, adverse side effects elicited by the administrationof the acamprosate extended release dosage form are reduced at leastabout 10%, 15%, 25%, 30%, 40% or 50% as compared to administration of anequivalent dose of an immediate release formulation comprisingacamprosate.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing release of acamproste calcium from extendedrelease dosage forms.

FIG. 2 is a graph showing release of acamproste calcium from extendedrelease dosage forms.

FIG. 3 is a graph showing plasma concentrations over time afteradministration of acamprosate calcium to dogs.

DETAILED DESCRIPTION

The various aspects and embodiments will now be fully described herein.These aspects and embodiments may, however, be embodied in manydifferent forms and should not be construed as limiting; rather, theseembodiments are provided so the disclosure will be thorough andcomplete, and will fully convey the scope of the present subject matterto those skilled in the art.

I. Definitions

It must be noted that, as used in this specification, the singular forms“a,” “an,” and “the” include plural referents unless the context clearlydictates otherwise.

Compounds useful in the compositions and methods include those describedherein in any of their pharmaceutically acceptable forms, includingisomers such as diastereomers and enantiomers, salts, solvates, andpolymorphs, as well as racemic mixtures and pure isomers of thecompounds described herein, where applicable.

“Optional” or “optionally,” as used herein, means that the subsequentlydescribed element, component or circumstance may or may not occur, sothat the description includes instances where the element, component, orcircumstance occurs and instances where it does not.

The terms “subject,” “individual” or “patient” are used interchangeablyherein and refer to a vertebrate, preferably a mammal. Mammals include,but are not limited to, humans.

The term “about”, particularly in reference to a given quantity, ismeant to encompass deviations of plus or minus five percent.

The term “fed mode,” as used herein, refers to a state which istypically induced in a patient by the presence of food in the stomach,the food-giving rise to two signals, one that is said to stem fromstomach distension and the other a chemical signal based on food in thestomach. It has been determined that once the fed mode has been induced,larger particles are retained in the stomach for a longer period of timethan smaller particles; thus, the fed mode is typically induced in apatient by the presence of food in the stomach. The fed mode isinitiated by nutritive materials entering the stomach upon the ingestionof food. Initiation is accompanied by a rapid and profound change in themotor pattern of the upper GI tract, over a period of 30 seconds to oneminute. The change is observed almost simultaneously at all sites alongthe G.I. tract and occurs before the stomach contents have reached thedistal small intestine. Once the fed mode is established, the stomachgenerates 3-4 continuous and regular contractions per minute, similar tothose of the fasting mode but with about a quarter to half the amplitude(Force). The pylorus is partially open, causing a sieving effect inwhich liquids and small particles flow continuously from the stomachinto the intestine while indigestible particles greater in size than thepyloric opening are retropelled and retained in the stomach. Thissieving effect thus causes the stomach to retain particles exceedingabout 1 cm in size for approximately 4 to 8 hours or more.Administration of a dosage form “with a meal,” as used herein, refers toadministration during or after a meal. When the dosage form isadministered after a meal, it may be administered about 1, 2, 3, 4, 5,10, 15 minutes after completion of a meal.

A drug “release rate,” as used herein, refers to the quantity of drugreleased from a dosage form or pharmaceutical composition per unit time,e.g., milligrams of drug released per hour (mg/hr). Drug release ratesfor drug dosage forms are typically measured as an in vitro rate ofdissolution, i.e., a quantity of drug released from the dosage form orpharmaceutical composition per unit time measured under appropriateconditions and in a suitable fluid. Drug release tests may be obtainedfor the dosage forms or pharmaceutical compositions described hereinusing, for example, a USP Apparatus I (basket at 75 rmp, 100 rmp or 150rpm), a USP Apparatus II (paddle at 50-100 rpm or 50 rpm, 75 rpm or 100rpm), or a USP Dissolution Apparatus III (reciprocating cylinder) or aUSP Disintegration tester. Tests are performed, for example, at about pH1.2 (modified simulated gastric fluid, or mSFG), about pH 4.5 (theapproximate pH of the stomach after a meal), about pH 6.8 or at about pH7.5. Such testing may also be performed, for example, at about 37° C. or25° C. Suitable aliquots of the release rate solutions are tested todetermine the amount of drug released from the dosage form orpharmaceutical composition. For example, the drug can be assayed orinjected into a chromatographic system to quantify the amounts of drugreleased during the testing intervals.

The terms “hydrophilic” and “hydrophobic” are generally defined in termsof a partition coefficient P, which is the ratio of the equilibriumconcentration of a compound in an organic phase to that in an aqueousphase. A hydrophilic compound has a P value less than 1.0, typicallyless than about 0.5, where P is the partition coefficient of thecompound between octanol and water, while hydrophobic compounds willgenerally have a P greater than about 1.0, typically greater than about5.0. The polymeric carriers herein are hydrophilic, and thus compatiblewith aqueous fluids such as those present in the human body.

The term “polymer” as used herein refers to a molecule containing aplurality of covalently attached monomer units, and includes branched,dendrimeric, and star polymers as well as linear polymers. The term alsoincludes both homopolymers and copolymers, e.g., random copolymers,block copolymers and graft copolymers, as well as uncrosslinked polymersand slightly to moderately to substantially crosslinked polymers, aswell as two or more interpenetrating cross-linked networks.

The term “swellable polymer,” as used herein, refers to a polymer thatwill swell in the presence of a fluid. It is understood that a givenpolymer may or may not swell when present in a defined drug formulation.Accordingly, the term “swellable polymer” defines a structural featureof a polymer which is dependent upon the composition in which thepolymer is formulated. Whether or not a polymer swells in the presenceof fluid will depend upon a variety of factors, including the specifictype of polymer and the percentage of that polymer in a particularformulation. For example, the term “polyethylene oxide” or “PEO” refersto a polyethylene oxide polymer that has a wide range of molecularweights. PEO is a linear polymer of unsubstituted ethylene oxide and hasa wide range of viscosity-average molecular weights. Examples ofcommercially available PEOs and their approximate molecular weights are:POLYOX® NF, grade WSR coagulant, approximate molecular weight 5 million,POLYOX® grade WSR 301, approximate molecular weight 4 million, POLYOX®grade WSR 303, approximate molecular weight 7 million, POLYOX® grade WSRN-60K, approximate molecular weight 2 million, and POLYOX® grade N-80K,approximate molecular weight 200,000. It will be understood by a personwith ordinary skill in the art that an oral dosage form which comprisesa swellable polymer will swell upon imbibition of water or fluid fromgastric fluid.

The terms “swellable” and “bioerodible” (or simply “erodible”) are usedto refer to the polymers used in the present dosage forms, with“swellable” polymers being those that are capable of absorbing water andphysically swelling as a result, with the extent to which a polymer canswell being determined by the molecular weight or degree of crosslinking(for crosslinked polymers), and “bioerodible” or “erodible” polymersreferring to polymers that slowly dissolve and/or gradually hydrolyze inan aqueous fluid, and/or that physically disentangle or undergo chemicaldegradation of the chains themselves, as a result of movement within thestomach or GI tract.

The term “plasticizer” as used herein includes any compounds capable ofplasticizing or softening a polymer or a binder used in the presentinvention. The use of plasticizers is optional, and can be included inthe dosage form to modify the properties and characteristics of thepolymers used in the coat(s) or core of the dosage form for convenientprocessing during manufacture of the coat(s) and/or the core of thedosage form. Once the coat(s) and/or core have been manufactured,certain plasticizers can function to increase the hydrophilicity of thecoat(s) and/or the core of the dosage form in the environment of use.During manufacture of the coat(s) and/or core, the plasticizer can lowerthe melting temperature or glass transition temperature (softening pointtemperature) of the polymer or binder. Plasticizers can be included witha polymer and lower its glass transition temperature or softening point.Plasticizers also can reduce the viscosity of a polymer. Plasticizerscan impart some particularly advantageous physical properties to thedosage forms of the invention. Examples of plasticizers include but arenot limited to triethyl citrate, cetyl alcohol and mixtures of cetylalcohol and triethyl citrate. Plasticizers may be present in the ERportion in an amount ranging from about 0.5 wt % to 5.0 wt %, about 1.0wt % to about 3.0 wt % or about 2.0 wt % to about 3.0 wt %.

The term “friability,” as used herein, refers to the ease with which atablet will break or fracture. The test for friability is a standardtest known to one skilled in the art. Friability is measured understandardized conditions by weighing out a certain number of tablets(generally 20 tablets or less), placing them in a rotating Plexiglasdrum in which they are lifted during replicate revolutions by a radiallever, and then dropped approximately 8 inches. After replicaterevolutions (typically 100 revolutions at 25 rpm), the tablets arereweighed and the percentage of formulation abraded or chipped iscalculated. The friability of the tablets, of the present invention, ispreferably in the range of about 0% to 3%, and values about 1%, or less,are considered acceptable for most drug and food tablet contexts.Friability which approaches 0% is particularly preferred.

The term “tap density” or “tapped density,” as used herein, refers to ameasure of the density of a powder. The tapped density of apharmaceutical powder is determined using a tapped density tester, whichis set to tap the powder at a fixed impact force and frequency. Tappeddensity by the USP method is determined by a linear progression of thenumber of taps.

The term “bulk density,” as used herein, refers to a property of powdersand is defined as the mass of many particles of the material divided bythe total volume they occupy. The total volume includes particle volume,inter-particle void volume and internal pore volume.

The term “capping,” as used herein, refers to the partial or completeseparation of top or bottom crowns of the tablet main body. Formultilayer tablets, capping refers to separation of a portion of anindividual layer within the multilayer tablet. Unintended separation oflayers within a multilayer tablet prior to administration is referred toherein as “splitting.”

The term “content uniformity,” as used herein refers to the testing ofcompressed tablets to provide an assessment of how uniformly themicronized or submicron active ingredient is dispersed in the powdermixture. Content uniformity is measured by use of USP Method (GeneralChapters, Uniformity of Dosage Forms), unless otherwise indicated. Aplurality refers to five, ten or more tablet compositions.

The terms “effective amount” or a “therapeutically effective amount”refer to the amount of drug or pharmacologically active agent to providethe desired effect without toxic effects. The amount of an agent that is“effective” may vary from individual to individual, depending on theage, weight, general condition, and other factors of the individual. Anappropriate “effective” amount in any individual may be determined byone of ordinary skill in the art using routine experimentation. An“effective amount” of an agent can refer to an amount that is eithertherapeutically effective or prophylactically effective or both.

By “pharmaceutically acceptable,” such as in the recitation of a“pharmaceutically acceptable carrier,” or a “pharmaceutically acceptableacid addition salt,” is meant a material that is not biologically orotherwise undesirable, i.e., the material may be incorporated into apharmaceutical composition administered to a patient without causing anyundesirable biological effects or interacting in a deleterious mannerwith any of the other components of the composition in which it iscontained. The term “pharmacologically active” (or simply “active”) asin a “pharmacologically active” derivative, refers to a derivativehaving the same type of pharmacological activity as the parent compoundand/or drug and approximately equivalent in degree. When the term“pharmaceutically acceptable” is used to refer to a derivative (e.g., asalt) of an active agent, it is to be understood that the compound ispharmacologically active as well. When the term, “pharmaceuticallyacceptable” is used to refer to an excipient, it implies that theexcipient has met the required standards of toxicological andmanufacturing testing or that it is on the Inactive Ingredient Guideprepared by the FDA, or comparable agency.

The terms “drug,” “active agent,” “therapeutic agent,” and/or“pharmacologically active agent” are used interchangeably herein torefer to any chemical compound, complex or composition that is suitablefor oral administration and that has a beneficial biological effect,preferably a therapeutic effect in the treatment or prevention of adisease or abnormal physiological condition. The terms also encompasspharmaceutically acceptable, pharmacologically active derivatives ofthose active agents specifically mentioned herein, including, but notlimited to, salts, esters, amides, prodrugs, active metabolites,analogs, and the like. When the terms “active agent,” “pharmacologicallyactive agent,” and “drug” are used, then, or when a particular activeagent is specifically identified, it is to be understood that applicantsintend to include the active agent per se as well as pharmaceuticallyacceptable, pharmacologically active salts, esters, amides, prodrugs,metabolites, analogs, etc.

The term “dosage form” refers to the physical formulation of the drugfor administration to the patient. Dosage forms include withoutlimitation, tablets, capsules, caplets, liquids, syrups, lotions,lozenges, aerosols, patches, enemas, oils, ointments, pastes, powdersfor reconstitution, sachets, solutions, sponges, and wipes. Within thecontext of the present invention, a dosage form comprising anacamprosate formulation will generally be administered to patients inthe form of tablets.

The term “dosage unit” refers to a single unit of the dosage form thatis to be administered to the patient. The dosage unit will be typicallyformulated to include an amount of drug sufficient to achieve atherapeutic effect with a single administration of the dosage unitalthough where the size of the dosage form is at issue, more than onedosage unit may be necessary to achieve the desired therapeutic effect.For example, a single dosage unit of a drug is typically, one tablet,one capsule, or one tablespoon of liquid. More than one dosage unit maybe necessary to administer sufficient drug to achieve a therapeuticeffect where the amount of drug causes physical constraints on the sizeof the dosage form.

“Delayed release” dosage forms are a category of modified release dosageforms in which the release of the drug is delayed after oraladministration for a finite period of time after which release of thedrug is unhindered. Delayed release dosage forms are frequently used toprotect an acid-labile drug from the low pH of the stomach or whereappropriate to target the GI tract for local effect while minimizingsystemic exposure. Enteric coating is frequently used to manufacturedelayed release dosage forms.

The terms “sustained release,” and “extended release” are usedinterchangeably herein to refer to a dosage form that provides forgradual release of a drug over an extended period of time. With extendedrelease dosage forms, the rate of release of the drug from the dosageform is reduced in order to maintain therapeutic activity of the drugfor a longer period of time or to reduce any toxic effects associatedwith a particular dosing of the drug. Extended release dosage forms havethe advantage of providing patients with a dosing regimen that allowsfor less frequent dosing, thus enhancing compliance. Extended releasedosage forms can also reduce peak-related side effects associated withsome drugs and can maintain therapeutic concentrations throughout thedosing period thus avoiding periods of insufficient therapeutic plasmaconcentrations between doses. Reference herein to a gastric retainedextended release (ER) dosage form refers to a dosage form describedherein which comprises an ER portion. In other words, a gastric retainedextended release dosage form may comprise both an ER and an IR portion,or both an ER portion and a swelling portion, etc.

The term “modified release” refers to a dosage form that includes bothdelayed and extended release drug products. The manufacture of delayed,extended, and modified release dosage forms are known to ordinary skillin the art and include the formulation of the dosage forms withexcipients or combinations of excipients necessary to produce thedesired active agent release profile for the dosage form.

The “gastric retentive” oral dosage forms described herein are a type ofextended release dosage form. Gastric retentive dosage forms arebeneficial for the delivery of drugs with reduced absorption in thelower GI tract or for local treatment of diseases of the stomach orupper GI tract. For example, in certain embodiments of gastric retentiveoral dosage forms of the present invention, the dosage form swells inthe gastric cavity and is retained in the gastric cavity of a patient inthe fed med so that the drug may be released for heightened therapeuticeffect. See, Hou et al., Crit. Rev. Ther. Drug Carrier Syst.20(6):459-497 (2003).

The term “enteric coat” as used herein is defined to mean a coating orbarrier applied to a dosage form that can control the location in thedigestive system where the active drug(s) is absorbed. For example, anenteric coating can be used to: (i) protect the drug from thedestructive action of the enzymes or low pH environment of the stomach;(ii) prevent nausea or bleeding associated with the irritation of thegastric mucosa by the drug; and/or (iii) deliver the drug in anundiluted form in the intestine. Based on these criteria, in certainembodiments, the enteric coated dosage form can be regarded as a type ofdelayed release dosage form. They differ from sustained release dosageforms in that with sustained release dosage forms, the drug release isextended over a period of time to maintain therapeutic blood levels andto decrease the incidence of side effects caused by a rapid release;whereas, with enteric coatings, the primary objective is to confine therelease of the drug to a predetermined region of the gastrointestinaltract. Enteric coatings work by presenting a surface that issubstantially stable at acidic pH, but breaks down at higher pH to allowrelease of the drug in the intestine.

The term “reverse enteric coat” as used herein is defined to mean acoating or barrier applied to a dosage form that can control thelocation in the digestive system where the active drug(s) is absorbed.Reverse enteric coatings work by presenting a surface that issubstantially stable at a pH above 5, but breaks down at a pH up toabout 5, to allow release of the drug in gastric juices. As such, thedrug is soluble, swellable and/or permeable in digestive fluids (e.g.,pH of about 5), and is substantially insoluble and/or stable at a pHhigher than 5.

The term “enteric polymer” as used herein is defined to mean a polymericsubstance that when used in an enteric coat formulation, issubstantially insoluble and/or substantially stable under acidicconditions exhibiting a pH of less than about 5 and which aresubstantially soluble or can decompose under conditions exhibiting a pHof about 5 or more. Non-limiting examples of such enteric polymersinclude carboxymethylethylcellulose, cellulose acetate phthalate,cellulose acetate succinate, methylcellulose phthalate,hydroxymethylethylcellulose phthalate, hydroxypropylmethylcellulosephthalate, hydroxypropylmethylcellulose acetate succinate, polyvinylalcohol phthalate, polyvinyl butyrate phthalate, polyvinyl acetalphthalate, a copolymer of vinyl acetate/maleic anhydride, a copolymer ofvinylbutylether/maleic anhydride, a copolymer of styrene/maleic acidmonoester, a copolymer of methyl acrylate/methacrylic acid, a copolymerof styrene/acrylic acid, a copolymer of methyl acrylate/methacrylicacid/octyl acrylate, a copolymer of methacrylic acid/methyl methacrylateand mixtures thereof. Enteric polymers can be used individually or incombination with other hydrophobic or hydrophilic polymers in an entericcoat, a normal release matrix core, a controlled release matrix core,and/or in a controlled release coat. Enteric polymers can be combinedwith other pharmaceutically acceptable excipients to either facilitateprocessing of a coat including the enteric polymer or to alter thefunctionality of the coat.

The in vivo “release rate” and in vivo “release profile” refer to thetime it takes for the orally administered dosage form, or the activeagent-containing layer of a bilayer or multilayer tablet (administeredwhen the stomach is in the fed mode) or the content of the activeingredient to be reduced to 0-10%, preferably 0-5%, of its original sizeor level, as may be observed visually using NMR shift reagents orparamagnetic species, radio-opaque species or markers, or radiolabels,or determined mathematically, such as deconvolution, upon its plasmaconcentration profiles.

The term “AUC” (i.e., “area under the curve,” “area under theconcentration curve,” or “area under the concentration-time curve”) is apharmacokinetic term used to refer a method of measurement ofbioavailability or extent of absorption of a drug based on a plot of anindividual or pool of individual's blood plasma concentrations sampledat frequent intervals; the AUC is directly proportional to the totalamount of unaltered drug in the patient's blood plasma. For example, alinear curve for a plot of the AUC versus dose (i.e., straight ascendingline) indicates that the drug is being released slowly into the bloodstream and is providing a steady amount of drug to the patient; if theAUC versus dose is a linear relationship this generally representsoptimal delivery of the drug into the patient's blood stream. Bycontrast, a non-linear (i.e. less than dose proportional) AUC versusdose curve indicates rapid release of drug such that some of the drug isnot absorbed, or the drug is metabolized before entering the bloodstream.

The term “Cmax” (i.e., “maximum concentration”) is a pharmacokineticterm used to indicate the peak concentration of a particular drug in theblood plasma of a patient.

The term “Tmax” (i.e., “time of maximum concentration” or “time ofCmax”) is a pharmacokinetic term used to indicate the time at which theCmax is observed during the time course of a drug administration. Aswould be expected, a dosage form that would include an immediate releaseas well as a gastric retentive component would have a shorter Tmax andhigher Cmax for an immediate release dosage form, but longer Tmax andlower Cmax for a purely gastric retentive dosage form.

“Preventing,” in reference to a disorder or unwanted physiological eventin a patient, refers specifically to inhibiting or significant reducingthe occurrence of symptoms associated with the disorder and/or theunderlying cause of the symptoms.

“Therapeutically effective amount,” in reference to a therapeutic agent,refers to an amount that is effective to achieve a desired therapeuticresult. Therapeutically effective amounts of a given agent willtypically vary with respect to factors such as the type and severity ofthe disorder or disease being treated and the age, gender, weight andother factors of the patient.

“Treating,” “treat,” and “treatment” refer to reduction in severityand/or frequency of symptoms, elimination of symptoms and/or underlyingcause, prevention of the occurrence of symptoms and/or their underlyingcause, and improvement or remediation of damage.

II. Gastric Retentive Dosage Form for the Extended Release ofAcamprosate

The pharmaceutical compositions described herein, i.e., gastric retaineddosage forms comprising acamprosate, provide extended or sustainedrelease of the acamprosate to the upper gastrointestinal tract. Thepresently described dosage forms provide for extended release of theacamprosate in the stomach wherein the dosage forms are comprised of apolymer matrix that swells upon imbibition of fluid to a size sufficientfor gastric retention. Thus, in formulating the dosage forms, it isdesirable to provide the properties which simultaneously allow: a) anextent of swelling to provide gastric retention over an extended period,and b) a rate of swelling and erosion that allows release of theacamprosate over a time period of approximately 6 to 12 hours.

IIa. Acamprosate

An acamprosate calcium dosage form currently marketed in the UnitedStates is sold as Campral®. Each CAMPRAL tablet contains 333 mgacamprosate calcium, which is equivalent to 300 mg acamprosate. Thesetablets are formulated as immediate release tablets, with therecommended dose between 2 tablets, 3 times daily.

Acamprosate calcium is a synthetic compound with a chemical structuresimilar to that of the endogenous amino acid homotaurine, which is astructural analogue of the amino acid neurotransmitter γ-aminobutyricacid and the amino acid neuromodulator taurine. Acamprosate calcium ishighly hydrophilic and is freely soluble in water. The calcium salt isalmost completely dissociated (98%) in hydrophilic media and the acetylhomotaurinic acid is a strong, completely dissociated acid, which meansthat it has a strongly charged functional group. Accordingly, it isthought that the low oral bioavailability of acamprosate is due to itspoor intestinal membrane permeability (see Zornoza et al., 2003, CNSDrug Reviews, 9:359-374; Chabenat et al., 1988, Meth. Find. Exp. Clin.Pharmacol., 10:311-317).

The absolute bioavailability of CAMPRAL after oral administration isabout 11%, with steady-state peak plasma concentrations after dosingwith 2×333 mg tablets 3 times daily averaging 350 ng/ml and occurring at3-8 hours post-dose (see CAMPRAL product insert). Interestingly,coadministration of CAMPRAL with food decreases bioavailability asmeasured by C_(max) and AUC, by approximately 42% and 23%, respectively.

Acamprosate has proven effective in treating alcohol dependence. Suchtreatment helps subjects suffering from alcohol dependence abstain fromalcohol ingestion. As acamprosate is effective in helping subjectsabstain from drinking alcohol only as long as the subjects hastherapeutically effective amounts of acamprosate in their blood, it isvery useful to have access to an extended release dosage form whichrequires fewer doses during a 24 hour period. More recent studiessuggest that acamprosate may also prove effective in the treatment ofother indications such as tinnitus, sleep apnea, levodopa-induceddyskinesias in Parkinson's disease, Alzheimer's disease, Huntington'sdisease, amyotrophic lateral sclerosis, cortical spreading depression,migraine, schizophrenia, anxiety disorders, motion disorders, tardivedyskinesia, spasticity, multiple sclerosis, various types pain, or bingeeating.

Described herein are oral dosage forms that provide sustained release ofacamprosate from a gastric retained dosage form into the stomach,allowing delivery of the acamprosate to the small intestine for at least8-12 hours. This release profile allows continual bathing of the smallintestine in acamprosate present at concentrations which aretherapeutically effective.

Design of a gastric retentive dosage form comprising acamprosate or atherapeutically acceptable salt thereof is challenging for multiplereasons. First, as noted above, the bioavailability of acamprosate isknown to decrease in the presence of food. Yet, gastric retentive dosageforms such as those described herein, rely on the use of food to inducethe fed mode, thereby reducing the diameter of the pyloric sphincter andpromoting retention of the swellable dosage form in the stomach.Accordingly, it becomes imperative to design the gastric retained dosageform to provide a release profile such that use of food to induce thefed mode does not interfere with achieving the desired pharmacokineticprofile.

Another complication is the presence of a sulphonic acid functionalgroup on the acamprosate. This group imparts a negative charge whichaffects the ability of the drug to be released from the dosage form at adesired rate. It becomes important to include excipients which allowsufficient swelling of the dosage form to promote retention in thestomach over an extended period of time while also providing the steadyand extended release of the acamprosate into stomach, thereby providingthe continual exposure of the drug to the walls of the upper smallintestine.

A gastric retained extended dosage form as described herein has theadded benefit of reduced side effects as compared to an immediaterelease dosage form, e.g., CAMPRAL. Side effects (adverse events) shownto occur as a rate of at least 3% than placebo in a CAMPRAL treatmentgroup include accidental injury, asthenia, pain, anorexia, diarrhea,flatulence, nausea, anxiety, depression, dizziness, dry mouth, insomnia,paresthesia, pruritus, and sweating (see CAMPRAL prescribinginformation). In one embodiment, administration of the extended releasegastric retained acamprosate dosage form described herein results inless than 3% of the patients experiencing one or more of the adverseevents as compared to patients receiving placebo in a controlledclinical trial, wherein the adverse event is accidental injury,asthenia, pain, anorexia, diarrhea, flatulence, nausea, anxiety,depression, dizziness, dry mouth, insomnia, paresthesia, pruritus,and/or sweating. In another embodiment, the reduced side effect observedwith administration of the gastric retained ER dosage form is

Moreover, the formulation of these pharmaceutical oral dosage forms mustresult in final products that meet the requirements of regulatoryagencies such as the Food and Drug Administration. For example, finalproducts must have a stable product that does not fracture duringstorage and transport. This is measured for tablets, in part, in termsof friability and hardness. Dosage forms must also meet the requirementsfor content uniformity, which essentially means that the dispersion ofthe active ingredient(s) is uniform throughout the mixture used to makethe dosage form, such that the composition of tablets formed from aparticular formulation does not vary significantly from one tablet toanother. The FDA generally requires a content uniformity within a rangeof 95% to 105%.

The dosage form as described here may comprise one or more swellablepolymers and are capable of swelling dimensionally unrestrained in thestomach upon contact with gastric fluid due to the component hydrophilicpolymers, for example, polyethylene oxide and/or hypromellose (alsoknown as hydroxypropyl methylcellulose or HPMC), and increase to a sizesufficient to be retained in the stomach in a fed mode.

Water-swellable polymers suitable for use herein are those that swell ina dimensionally unrestrained manner upon contact with water Suchpolymers may also gradually erode over time. Examples of such polymersinclude polyalkylene oxides, such as polyethylene glycols, particularlyhigh molecular weight polyethylene glycols; cellulose polymers and theirderivatives including, but not limited to, hydroxyalkyl celluloses,hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, carboxymethylcellulose,microcrystalline cellulose; polysaccharides and their derivatives;chitosan; poly(vinyl alcohol); xanthan gum; maleic anhydride copolymers;poly(vinyl pyrrolidone); starch and starch-based polymers;maltodextrins; poly(2-ethyl-2-oxazoline); poly(ethyleneimine);polyurethane; hydrogels; crosslinked polyacrylic acids; and combinationsor blends of any of the foregoing.

Further examples are copolymers, including block copolymers and graftpolymers. Specific examples of copolymers are PLURONIC® and TECTONIC®,which are polyethylene oxide-polypropylene oxide block copolymersavailable from BASF Corporation, Chemicals Div., Wyandotte, Mich., USA.Further examples are hydrolyzed starch polyacrylonitrile graftcopolymers, commonly known as “Super Slurper” and available fromIllinois Corn Growers Association, Bloomington, Ill., USA.

Preferred swellable, erodible hydrophilic polymers suitable for formingthe gastric retentive portion of the dosage forms described herein arepoly(ethylene oxide), hydroxypropyl methyl cellulose, and combinationsof poly(ethylene oxide) and hydroxypropyl methyl cellulose.Poly(ethylene oxide) is used herein to refer to a linear polymer ofunsubstituted ethylene oxide. The molecular weight of the poly(ethyleneoxide) polymers can range from about 9×10⁵ Daltons to about 8×10⁶Daltons. Exemplary molecular weight poly(ethylene oxide) polymersinclude about 9×10⁵ Daltons (e.g., SENTRY™ POLYOX™ WSR 1105, NF Grade,Dow Chemical), 2×10⁶ Daltons (e.g., SENTRY™ POLYOX™ WSR N60K, NF Grade,Dow Chemical), 2×10⁶ Daltons (e.g., SENTRY™ POLYOX™ WSR 301, NF Grade,Dow Chemical), and 7×10⁶ Daltons (e.g., SENTRY™ POLYOX™ WSR N60K, NFGrade, Dow Chemical). The viscosity of a 1% water solution of thepolymer at 25° C. preferably ranges from 4500 to 7500 centipoise.

Dosage forms prepared for oral administration according to the presentdisclosure will generally contain other inactive additives (excipients)such as binders, lubricants, disintegrants, fillers, stabilizers,surfactants, coloring agents, and the like.

Binders are used to impart cohesive qualities to a tablet, and thusensure that the tablet or tablet layer remains intact after compression.Suitable binder materials include, but are not limited to, starch(including corn starch and pregelatinized starch), gelatin, sugars(including sucrose, glucose, dextrose and lactose), polyethylene glycol,waxes, and natural and synthetic gums, e.g., acacia sodium alginate,polyvinylpyrrolidone, cellulosic polymers (including hydroxypropylcellulose, hydroxypropyl methylcellulose, methyl cellulose,microcrystalline cellulose, ethyl cellulose, hydroxyethyl cellulose, andthe like), and Veegum. Examples of polyvinylpyrrolidone includepovidone, copovidone and crospovidone.

Lubricants are used to facilitate tablet manufacture, promoting powderflow and preventing particle capping (i.e., particle breakage) whenpressure is relieved. Useful lubricants are magnesium stearate (in aconcentration of from 0.25 wt % to 3 wt %, 0.2 wt % to 1.5 wt %, orabout 1.0 wt %), calcium stearate, stearic acid, and hydrogenatedvegetable oil (e.g., comprised of hydrogenated and refined triglyceridesof stearic and palmitic acids at about 1 wt % to 5 wt % or less thanabout 2 wt %). Disintegrants are used to facilitate disintegration ofthe tablet, thereby increasing the erosion rate relative to thedissolution rate, and are generally starches, clays, celluloses, algins,gums, or crosslinked polymers (e.g., crosslinked polyvinyl pyrrolidone).Fillers include, for example, materials such as silicon dioxide,titanium dioxide, alumina, talc, kaolin, powdered cellulose, andmicrocrystalline cellulose, as well as soluble materials such asmannitol, urea, sucrose, lactose, lactose monohydrate, dextrose, sodiumchloride, and sorbitol. Solubility-enhancers, including solubilizers perse, emulsifiers, and complexing agents (e.g., cyclodextrins), may alsobe advantageously included in the present formulations. Stabilizers, aswell known in the art, are used to inhibit or retard drug decompositionreactions that include, by way of example, oxidative reactions.

In other embodiments, the excipients of the presently described dosageforms include one or more excipients which carry a charge opposite thatof the acamprosate for pharmaceutically acceptable salt thereof. In someembodiments, the charged excipient is positively charged. As an example,a cationic excipient may include a polymeric quaternary ammoniumcompound. Other cationic polymers may include chitosan or a derivativethereof including, for example, trimethylchitosan and quarternisedchitosan, and chitosan-derived materials including, for example, thosetaught in U.S. Pat. No. 5,747,475. Either high or low molecular weightchitosan products can be used in the pharmaceutical formulations of thepresent invention and are readily available in pharmaceutical grade fromsuppliers located world-wide. It is envisioned that release of thecharged acamprosate may be further slowed via ionic interactions withone or more oppositely charged excipients.

Also envisioned is incorporation of the acamprosate or pharmaceuticallyacceptable salt thereof into the polymer matrix using hot-melt extrusion(HME) (see Vervaet et al., 2008, DOSIS, 24:119-123). HME allows thecontinuity of the hot-stage extrusion technique as the different processsteps (mixing, melting, homogenizing and shaping) are carried out on asignle machine. This facilitates the production of matrices withexcellent homogeneity. Polymers which can be processed via HME tofunction as part of a release-controlling matrix include but are notlimited to synthetic cellulose derivatives (e.g., ethyl cellulose,hydroxypropylmethyl cellulose, cellulose-acetobutyrate), methacrylates,polyethylene oxides, polyvinylacetate, poly(lactide-co-glycolide),starch, lipids, and waxes. HME may also include combining the polymerwith a plasticizer to optimize the thermoplastic properties of thepolymer.

In one embodiment, a hot-melt process is performed in which the cationicpolymer Eudragit RS (or RL) PO is melted together with the acamprosatecalcium. The ionic interactions between the sulfonic acid group on theacamprosate and the quartinary amino of the Eudragit may slow release ofthe acamprosate from the tablet, as during the melt process theacamprosate and polymer are miscible. A hot melt process including ahigh molecular weight rate-controlling polymer such as POLYOX 303, inthe presence of the acamprosate and/or other insoluble excipients, mayresults in a dosage form in which the rate of water penetration isfurther slowed, thereby slowing the rate of acamprosate release from thedosage form.

The gastric retentive dosage form may be a single layer, bilayer, ormultilayer tablet or it may be a capsule. Multilayer tablets includetablets having a shell-and-core configuration in which a core is fullyencased by a shell. Tablets may also have a coating with or without thepharmaceutically active agent. The tablet comprises a gastric retentivelayer which comprises acamprosate or acamprosate calcium dispersed in amatrix comprised of at least one hydrophilic polymer which swells uponimbibition of fluid.

In one embodiment, a dosage form is formulated to have a dual-matrixconfiguration (“shell-and-core”) as described in US publication US2003/0104062 (herein incorporated by reference). One matrix forms a coreof polymeric material in which the acamprosate or acamprosate calcium isdispersed and the other matrix forms a casing that surrounds and fullyencases the core, the casing being of polymeric material that swellsupon imbibition of water (and hence gastric fluid) to a size largeenough to promote retention in the stomach during the fed mode, theshell and core being configured such that the drug contained in the coreis released from the dosage form by diffusion through the shell. Theshell is sufficient thickness and strength that it is not disrupted bythe swelling and remains intact during substantially the entire periodof drug release. The shell may or may not contain the acamprosate.

Water-swellable polymers useful in the preparation of the shell-and-coredosage form include polymers that are non-toxic and, at least in thecase of the shell, polymers that swell in a dimensionally unrestrictedmanner upon imbibition of water. The core polymer may also be a swellingpolymer, and if so, compatible polymers will be selected that will swelltogether without disrupting the integrity of the shell. The core andshell polymers may be the same or different, and if the same, they mayvary in molecular weight, crosslinking density, copolymer ratio, or anyother parameter that affects the swelling rate, so long as any swellingoccurring in the core causes substantially not splitting of the shell.

In one embodiment, a tablet having an immediate release layer encased byan extended release gastric retained layer as a shell is manufactured.

In one embodiment, a tablet is formulated to have an extended releasegastric retained (GR) layer spray-coated with an immediate release (IRlayer) to provide 12-hour release of the acamprosate. In a furtherembodiment, the tablet contains 750 mg acamprosate, with 75 mg, 100 mg,125 mg, or 150 mg acamprosate in the IR layer and 675 mg, 650 mg, 625mg, or 600 mg acamprosate, respectively, in the GR layer.

In one embodiment, an oral dosage form is formulated as a pulsatilerelease dosage form, as described in U.S. Patent Publication No.2009/028941 (incorporated herein by reference). In this embodiment, theoral dosage form may be comprised of: 1) a plurality of immediaterelease, enteric coated beads containing acamprosate, dispersed in ahydrophilic polymer that swells unrestrained dimensionally in water; 2)a series of inserts, each containing a plurality of immediate releasebeads containing the acamprosate, and each comprised of a swellablehydrophilic polymeric matrix, wherein the inserts are stacked to providepulses of acamprosate over an extended period of time; and 3) aswellable hydrophilic matrix comprised of two or more regions, eachregion containing a dose of acamprosate, wherein the regions vary insize and position within the matrix to effect pulsed release of theacamprosate over an extended period of time.

In another embodiment, the gastric retained dosage form is a floatingdosage form. Floatation of drug delivery systems as a gastroretentivemechanism has been widely used, These systems, also known ashydro-dynamically balanced, are buoyant on the gastric fluid and delaytheir emptying through the pyloric sphincter by swelling and expanding.Several approaches are currently used to prolong gastric retention time.These include floating drug delivery systems, also known ashydrodynamically balanced systems, swelling and expanding systems,polymeric bioadhesive systems, modified-shape systems, high-densitysystems, and other delayed gastric emptying systems. For example, Daveet al. (2004, AAPS PharmSciTech; 5:1-6) report on a gastroretentive drugdelivery system of ranitidine hydrochloride using the principles ofbuoyant preparation, wherein guar gum, xanthan gum, and hydroxypropylmethylcellulose were evaluated for gel-forming properties, sodiumbicarbonate was used as a gas-generating agent, and the effects ofcitric acid and stearic acid on drug release profile and floatingproperties were investigated. Similarly, Narendra et al. (2006, AAPSPharmSciTech, 7:E1-7) report on the development of an optimized gastricfloating drug delivery system containing metoprolol tartrate as a modeldrug, wherein the dosage form was prepared as a bilayer tabletcomprising a drug-loading layer and a floating layer in a suitable ratioto provide a bulk density lower than that of gastric fluids to remainbuoyant on the stomach contents. Buoyancy is a result of a reduction inmatrix density. Floatable delivery systems have been designed as singleand multiple-unit devices.

Gastric retained extended release dosage forms may also be formulated asosmotic dosage forms such as an elementary osmotic dosage form or apush-pull osmotic pump. For example, U.S. Pat. Nos. 3,845,770 and3,916,899 issued to Theeuwes and Higuchi pertains to an osmotic dosageform for delivering various drugs to a patient environment of use. Thedosage forms disclosed in these patents are manufactured comprising awall that surrounds a compartment comprising a drug with an exit in thewall for delivering the drug to a patient. In U.S. Pat. Nos. 4,008,719;4,014,334; 4,058,122; 4,116,241; and 4,160,452 patentees Theeuwes andAyer made available dosage forms comprising an inside and an outsidewall made of poly(cellulose acylate) for delivering a dosage of drug toa patient in need thereof.

U.S. Pat. No. 6,245,357 describes osmotic dosage forms comprising a drugcompartment and a pharmaceutically acceptable polymer hydrogel(maltodextrin, polyalkylene oxide, polyethylene oxide,carboxyalkylcellulose), contained within a bilayer interior wall andexterior wall and having a passageway, where the polymer exhibits anosmotic pressure gradient across the bilayer interior wall and exteriorwall thereby imbibing fluid into the drug compartment to form a solutionor a suspension comprising the drug that is hydrodynamically andosmotically delivered through a passageway from the dosage form. Incertain embodiments, the dosage form further comprises a pushdisplacement layer which expands to expel the drug from the dosage form.This patent describes that the interior wall of these dosage formscomprises a pore former which provides for increased permeability of thedosage form to water to compensate for the decrease in osmotic drivingforce that occurs as the osmagent and/or drug dissolves and is releasedfrom the dosage form. The dosage form was reported to exhibit a slowdrug delivery until the osmotically-sensitive pore former dissolved orwas leached from the inner wall. The eluted pore former caused thepermeability of the inner wall to increase, which correspondingly causedthe net permeability of the bilaminated inner wall-outer wall toincrease over time. This increase in permeability was reported to offsetany decrease in osmotic activity and produced a linear drug deliveryprofile. In addition, this patent describes dosage forms suitable foradministering analgesic agents having a drug compartment comprising anopioid analgesic and a nonopioid analgesic and a polymer hydrogel,coated with an interior wall containing a pore former and an exteriorwall.

Various devices and methods have been described having intended utilitywith respect to applications with high drug loading. For example, U.S.Pat. Nos. 4,892,778 and 4,940,465 describe dispensers for delivering abeneficial agent to an environment of use that include a semipermeablewall defining a compartment containing a layer of expandable materialthat pushes a drug layer out of the compartment formed by the wall. Theexit orifice in the device is substantially the same diameter as theinner diameter of the compartment formed by the wall. Additionally, U.S.Pat. No. 6,368,626 describes high drug loading dosage forms forproviding controlled release of active agents. This patent describesthat the active agent is uniformly released from the dosage forms over aprolonged period of time, and that the release of the active agent froma dosage form does not vary positively or negatively by more than 30%from the mean rate of release of the active agent over a prolongedperiod of time, as determined in a USP Type 7 Interval ReleaseApparatus.

In one embodiment, one means for releasing the acamprosate from thedosage form includes a means for generating gas, which means forgenerating gas is surrounded by, for example, a semipermeable membrane.In operation, when the gas generating means imbibes water and/or aqueousbiological fluids, the means for generating gas reacts and generatesgas, thereby enlarging and expanding the at least one means for forciblydispensing the tetrabenazine unidirectionally or multidirectionally. Themeans for generating a gas includes any compound or compounds, which canproduce effervescence, such as for example, at least one solid acidcompound and at least one solid basic compound, which in the presence ofa fluid can react to form a gas, such as for example, carbon dioxide.Examples of acid compounds include, organic acids such as malic,fumaric, tartaric, itaconic, maleic, citric, adipic, succinic andmesaconic, and inorganic acids such as sulfamic or phosphoric, also acidsalts such as monosodium citrate, potassium acid tartrate and potassiumbitartrate. The basic compounds include, for example, metal carbonatesand bicarbonates salts, such as alkali metal carbonates andbicarbonates. The acid and base materials can be used in any convenientproportion from about 1 to about 200 parts of the at least one acidcompound to the at least one basic compound or from about 1 to about 200parts of the at least one basic compound to the at least one acidcompound. The means for generating gas is known.

In one embodiment, the gastric retained dosage form of acamprosate is acapsule dosage form that allows for the extended release of acamprosatein the stomach and comprises: (a) at least one component that expands oncontact with gastric juice and contains an agent capable of releasingcarbon dioxide or nitrogen, acamprosate or a pharmaceutically acceptablesalt thereof; (b) at least one hydrophilic membrane in the form of asachet which contains component (a), expands by inflation, floats on theaqueous phase in the stomach and is permeable to gastric juice and; (c)capsule dosage form which contains components (a) and (b) and whichdisintegrates without delay in the stomach under the action of gastricjuice. Component (a) may also contain a pharmaceutically acceptablehydrophilic swelling agent such as lower alkyl ethers of cellulose,starches, water-soluble aliphatic or cyclic poly-N-vinylamides,polyvinyl alcohols, polyacrylates, polymethacrylates, polyethyleneglycols and mixtures thereof, as well as other materials used in themanufacture of pharmaceutical dosage forms. Further details regarding anexample of this type of dosage form can be found in Sinnreich, U.S. Pat.No. 4,996,058.

Dosage forms described herein can contain other materials that modifythe physical form of the dosage, for example, as coatings. Thus, dosageforms, for example drug particles dispersed in a swellable hydrophilicmatrix, can be coated with sugar, shellac, sustained and other entericcoating agents. Materials used in preparing these compositions should bepharmaceutically pure and nontoxic in the amounts used. Enteric coatingsare well known in the art and can be selected for use based on the pH atwhich the enteric coating will dissolve in the gastrointestinal tract.The enteric coating is insoluble in a strongly acidic environment, suchas the stomach, and releases the active agent in a more basic or lessacidic environment, such as small intestine. This protects the activeagent from degradation and provides a stable formulation.

The gastric retained dosage forms described herein are designed toprovide release of acamprosate or a pharmaceutically acceptable saltthereof, to provide a pharmacokinetic profile which optimizes effectivetreatment of a subject suffering from, for example, alcohol dependence,tinnitus, sleep apnea, levodopa-induced dyskinesias in Parkinson'sdisease, Alzheimer's disease, Huntington's disease, amyotrophic lateralsclerosis, cortical spreading depression, migraine, schizophrenia,anxiety disorders, motion disorders, tardive dyskinesia, spasticity,multiple sclerosis, various types pain, or binge eating.

As seen in the examples below, a gastric retained extended releasedosage form may provide bioavailability of the acamprosate such that anAUC0-t of from about 20,000 ng·h/ml to about 60,000 ng·h/ml, from about30,000 ng·h/ml to about 50,000 ng·h/ml, or from about 40,000 ng·h/ml toabout 45,000 ng·h/ml is achieved. Importantly, the Tmax is shifted ascompared to the Tmax achieved upon administration of an IR dosage form.For example, the Tmax achieved by administering a gastric retainedextended release dosage form comprising acamprosate may occur betweenabout 2 h to 10 h, about 3 h to about 8 h, between about 4 h to about 7h, or between about 5 h to about 6 h. The Cmax achieved by dosing of thesubject with the gastric retained extended release acamprosate dosageform may range from about 1000 ng/ml to about 10,000 ng/ml, about 2000ng/ml to about 8000 ng/ml, about 3000 ng/ml to about 6000 ng/ml or fromabout 4000 ng/ml to about 5500 ng/ml.

III. Methods for Making the Dosage Forms

The presently described dosage forms provide for extended release ofacamprosate in the stomach wherein the dosage forms are comprised of apolymer matrix that swells upon imbibition of fluid to a size sufficientfor gastric retention. Thus, in formulating the dosage forms, it isdesirable to provide the properties which simultaneously allow: a) anextent of swelling to provide gastric retention over an extended period,and b) a rate of swelling and erosion that allows release of theacamprosate over a time period of approximately 6 hours to 14 hours, andpreferable 8 hours to 12 hours.

Moreover, the formulation of these pharmaceutical oral dosage formspreferably result in final products that meet the requirements ofregulatory agencies such as the Food and Drug Administration. Forexample, final products desirably have a stable product that does notfracture during storage and transport. This is measured for tablets, inpart, in terms of friability and hardness. Dosage forms preferably alsosatisfy requirements for content uniformity, which essentially meansthat the dispersion of the active ingredient(s) is uniform throughoutthe mixture used to make the dosage form, such that the composition oftablets formed from a particular formulation does not vary significantlyfrom one tablet to another. The FDA requires a content uniformity withina range of 95% to 105%.

The ability to formulate a pharmaceutical oral dosage form which bothdelivers the therapeutically effective ingredient over a desired periodof time and meets FDA requirements depends, in part and in someembodiments, upon the process by which the product is made.

In the case of gastric retentive tablets containing acamprosate, asdisclosed herein, tablets may be made through direct compression orfollowing a granulation procedure. Direct compression is used with agroup of ingredients that can be blended, placed onto a tablet press,and made into a perfect tablet without any of the ingredients having tobe changed. Powders that can be blended and compressed are commonlyreferred to as directly compressible or as direct-blend formulations.When powders do not compress correctly, a granulation technique isconsidered.

Granulation is a manufacturing process which increases the size andhomogeneity of active pharmaceutical ingredients and excipients whichcomprise a solid dose formulation. The granulation process, which isoften referred to as agglomeration, changes physical characteristics ofthe dry formulation, with the aim of improving manufacturability, andtherefore, product quality.

Granulation technology can be classified into one of two basic types:wet granulation and dry granulation. Wet granulation is by far the moreprevalent agglomeration process utilized within the pharmaceuticalindustry. Most wet granulation procedures follow some basic steps; thedrug(s) and excipients are mixed together, and a binder solution isprepared and added to the powder mixture to form a wet mass. The moistparticles are then dried and sized by milling or by screening through asieve. In some cases, the wet granulation is “wet milled” or sizedthrough screens before the drying step. There are four basic types ofwet granulation; high shear granulation, fluid bed granulation,extrusion and spheronization and spray drying.

A. Dry Granulation

The dry granulation process involves three basic steps; the drug(s) andexcipients(s) are mixed (along with a suitable binder if needed) andsome form of lubrication, the powder mixture is compressed into dry“compacts,” and then the compacts are sized by a milling step. The twomethods by which dry granulation can be accomplished are slugging androller compaction.

B. Fluid Bed (Wet) Granulation

The fluid bed granulation process involves the suspension ofparticulates within an air stream while a granulation solution issprayed down onto the fluidized bed. During the process, the particlesare gradually wetted as they pass through the spay zone, where theybecome tacky as a result of the moisture and the presence of binderwithin the spray solution. These wetted particles come into contactwith, and adhere to, other wetted particles resulting in the formationof particles.

A fluid bed granulator consists of a product container into which thedry powders are charged, an expansion chamber which sits directly on topof the product container, a spray gun assembly, which protrudes throughthe expansion chamber and is directed down onto the product bed, and airhandling equipment positioned upstream and downstream from theprocessing chamber.

The fluidized bed is maintained by a downstream blower which createsnegative pressure within the product container/expansion chamber bypulling air through the system. Upstream, the air is “pre-conditioned”to target values for humidity, temperature and dew point, while specialproduct retention screens and filters keep the powder within the fluidbed system.

As the air is drawn through the product retention screen it “lifts” thepowder out of the product container and into the expansion chamber.Since the diameter of the expansion chamber is greater than that of theproduct container, the air velocity becomes lower within the expansionchamber. This design allows for a higher velocity of air to fluidize thepowder bed causing the material to enter the spray zone wheregranulation occurs before loosing velocity and falling back down intothe product container. This cycle continues throughout the granulationprocess.

The fluid bed granulation process can be characterized as having threedistinct phases; pre-conditioning, granulation and drying. In theinitial phase, the process air is pre-conditioned to achieve targetvalues for temperature and humidity, while by-passing the productcontainer altogether. Once desired or optimal conditions are met, theprocess air is re-directed to flow through the product container, andthe process air volume is adjusted to a level which will maintainsufficient fluidization of the powder bed. This pre-conditioning phasecompletes when the product bed temperature is within the target rangespecified for the process.

In the next phase of the process, the spraying of the granulatingsolution begins. The spray rate is set to a fall within a pre-determinedrange, and the process continues until all of the solution has beensprayed into the batch. It is in this phase where the actualgranulation, or agglomeration, takes place.

Once the binder solution is exhausted, the product continues to befluidized with warm process air until the desired end-point for moisturecontent is reached. This end-point often correlates well with productbed temperature, therefore in a manufacturing environment, the processcan usually be terminated once the target product bed temperature isreached. A typical fluid bed process may require only about thirty toforty-five minutes for the granulation step, plus ten to fifteen minuteson either side for pre-conditioning and drying.

As with any of the wet granulation processes, a variable is the amountof moisture required to achieve successful agglomeration. The fluid bedgranulation process preferably provides a “thermodynamic” balancebetween process air temperature, process air humidity, process airvolume and granulation spray rate. While higher process air temperatureand process air volume add more heat to the system and remove moisture,more granulating solution and a higher solution spray rate add moistureand remove heat via evaporative cooling. These are process parameterswhich are preferably evaluated as a manufacturing process is developed,and a key to understanding the interdependency of each variable.

Additional factors affecting the outcome of the fluid bed granulationprocess are the amount and type of binder solution, and the method bywhich the binder is incorporated within the granulation. Other processvariables are the total amount of moisture added through the process,and the rate at which the moisture content is increased. Theseparameters can have an effect on the quality and the characteristics ofthe granulation. For instance, a wetter fluid bed granulation processtends to result in a stronger granule with a higher bulk density.However, an overly aggressive process, where moisture is added toorapidly, can loose control over achieving the final particle size andparticle size distribution objectives.

C. High Shear Granulation

Most pharmaceutical products manufactured by wet granulation utilize ahigh shear process, where blending and wet massing are accomplished bythe mechanical energy generated by an impeller and a chopper. Mixing,densification and agglomeration are achieved through the “shear” forcesexerted by the impeller; hence the process is referred to as high sheargranulation.

The process begins by adding the dry powders of the formulation to thehigh shear granulator, which is a sealed “mixing bowl” with an impellorwhich rotates through the powder bed, and a chopper blade which breaksup over-agglomerates which can form during the process. There aretypically three phases to the high shear process; dry mixing, solutionaddition, or wet massing and high shear granulation.

In the first phase, dry powders are mixed together by the impeller bladewhich rotates through the powder bed. The impeller blade is positionedjust off the bottom of the product container. There is a similartolerance between the tips of the impeller blade and the sides of thecontainer. The impeller blades rotation through the powder bed creates a“roping” vortex of powder movement. The dry mixing phase typically lastsfor only a few minutes.

In the second phase of the process, a granulating liquid is added to thesealed product container, usually by use of a peristaltic pump. Thesolution most often contains a binder with sufficient viscosity to causethe wet massed particles to stick together or agglomerate. It is commonfor the solution addition phase to last over a period of from three tofive minutes. While the impeller is rotating rather slowly during thisstep of the process, the chopper blade is turning at a fairly high rateof speed, and is positioned within the product container to chop upover-sized agglomerates, while not interfering with the impellersmovement.

Once the binder solution has been added to the product container, thefinal stage of the granulation process begins. In this phase, high shearforces are generated as the impeller blades push through the wet massedpowder bed, further distributing the binder and intimately mixing theingredients contained therein. The impeller and chopper tool continue torotate until the process is discontinued when the desired granuleparticle size and density end-points are reached. This end-point isoften determined by the power consumption and/or torque on the impeller.

Once the high shear granulation process has been completed, the materialis transferred to a fluid bed dryer, or alternatively, spread out ontotrays which are then placed in a drying oven, where the product is drieduntil the desired moisture content is achieved, usually on the order of1-2% as measured by Loss On Drying technique.

A variable which affects the high shear process is the amount ofmoisture required to achieve a successful granulation. A key to theprocess is having the right amount of moisture to allow foragglomeration to occur. Too little moisture will result in anunder-granulated batch, with weak bonds between particles and smaller,to non-existent particles, with properties similar to those of the drypowder starting materials. On the other hand, excess moisture can resultin a “crashed” batch with results varying from severe over-agglomerationto a batch which appears more like soup.

Other formulation parameters affecting the outcome of the high sheargranulation process are the amount and type of binder solution, and themethod by which the binder is incorporated within the granulation. Forexample, it is possible to include some of the binder in the dry powdermixture as well as in the granulating solution, or it may beincorporated only in the granulating solution or only in the dry powder,as is the case where water is used as the granulating solution.

The high shear granulation process parameters which are variable includeimpeller and chopper speeds, the solution addition rate, and the amountof time allocated to the various phases of the process. Of these,variables for consideration are the solution addition rate and theamount of time the wet massed product is under high shear mixing

D. Extrusion and Spheronization

This specialized wet granulation technique involves multiple processingsteps and was developed to produce very uniform, spherical particlesideally suited for multi-particulate drug delivery of delayed andsustained release dosage forms.

Similar to high shear granulation initially, the first step involves themixing and wet massing of the formulation. Once this step is complete,the wet particles are transferred to an extruder which generates veryhigh forces used to press the material out through small holes in theextruder head. The extrudate is of uniform diameter and is thentransferred onto a rotating plate for spheronization. The forcesgenerated by the rotating plate initially break up the extrudedformulation strands into uniform lengths. Additional dwell time withinthe spheronizer creates particles which are quite round and very uniformin size. These pellets or spheres must then be dried to the targetmoisture content, usually within a fluid bed system.

Particles produced in this manner tend to be very dense, and have acapacity for high drug loading, approaching 90% or more in some cases.Preferably, particle size is uniform, and the size distribution isnarrow, as compared to other granulation approaches. This qualityassures consistent surface area within and between batches, which isdesired when functional coatings are subsequently applied to createsustained release formulations, delayed release formulations andformulations designed to target a specific area within the body.

Uniform surface area is desired because the pharmaceutical coatingprocess endpoint is determined not by coating thickness, but by thetheoretical batch weight gain of the coating material. If the batchsurface area is consistent, then the coating thickness will also beconsistent for a given weight gain, and coating thickness is the primaryvariable in determining the functionality of the coating system, whetherthe goal is controlling the duration of sustained release formulationsor imparting an acid resistant characteristic to “beads” necessary toprotect certain compounds which would otherwise be severely degraded inthe presence of the acidic environment of the stomach.

E. Spray Drying

Spray drying is a unique and specialized process which converts liquidsinto dry powders. The process involves the spraying of very finelyatomized droplets of solution into a “bed” or stream of hot process airor other suitable gas. Not typically utilized for the conventionalgranulation of dosage form intermediates, spray drying has gainedacceptance within the industry as a robust process which can improvedrug solubility and bioavailability.

Spray drying can be used to create co-precipitates of a drug/carrierwhich can have improved dissolution and solubility characteristics. Inaddition, the process can also be useful as a processing aid. Forexample, it is much more difficult to maintain the uniformity of a drugin suspension, as compared to the same compound in solution. One mayhave a need to develop an aqueous coating or drug layering processutilizing a drug which is otherwise not soluble in water. By creating aco-precipitate of the drug and a suitable water soluble carrier, often alow molecular weight polymer, the co-precipitate will remain in solutionthroughout the manufacturing process, improving uniformity of the spraysolution and the dosage form created by the coating process. Uniformityis particularly desired where lower doses of potent compounds areintended to be coated onto beads or tablet cores.

This same process may be used to enhance the solubility andbioavailability of poorly soluble drugs. By complexing certainexcipients and the active ingredient within a solvent system which isthen spray dried, it is possible to enhance the drugs absorption withinthe body. Selection of the solvent system, the complexing agent(s) andthe ratios utilized within the formulation are all formulation variableswhich determine the effectiveness of solubility enhancement utilizingthe spray drying technique. Process parameters which also have an effecton drug solubility are the temperatures of the spray solution andprocess gas, the spray rate and droplet size and the rate ofre-crystallization. The spray dried granulations created by thesetechniques can then be incorporated into capsules or tablets byconventional manufacturing processes.

IV. Methods of Making the Extended Release Gastric Retentive DosageForms Disclosed Herein

In one aspect, a method of making a gastric retentive extended-releasedosage form as a single layer tablet comprising dry blending of theacamprosate with the binder is provided. The blended material is thengranulated in the presence of water using, for example, a KitchenAid®blender. The granulated particles are then dried overnight, screened andblended with additional excipients as needed to form a mixture which isthen compressed to form tablets.

Extended release polymer matrices comprising acamprosate are made usingone or a combination of one or more of the following: POLYOX® 1105(approximate molecular weight of 900,000 Daltons), POLYOX® N-60K(approximate molecular weight of 2,000,000 Daltons), POLYOX® WSR-301(approximate molecular weight of 4,000,000 Daltons), or POLYOX® WSR-303(approximate molecular weight of 7,000,000 Daltons).

After granulation of the active ingredient and subsequent blending theadditional excipients, batches are characterized with respect toproperties such as final Loss on Drying (LOD), bulk density, tapdensity, and particle size.

Loss on Drying (LOD) is determined after each granulation using theMoisture Analyzer. A 1 g samples are taken and loaded into the moistureanalyzer. The sample is run for 5 minutes at a temperature of 105° C.

Bulk and tap densities can be determined as follows. A graduatedcylinder is filled with a certain amount of material (82-88 g), and thevolume recorded to determine the material bulk density. Tap density canbe determined with a help of a Tap Density Tester by exposing thematerial to 100 taps per test and recording the new volume.

Particle size determination is performed immediately after granulation,after sieving through 20 mesh screen to remove agglomerates. Particlediameter is determined with a sieve-type particle diameter distributiongauge using sieves with openings of 44, 53, 75, 106, 150, and 250 mesh.Fractions are weighed on Mettler balance to estimate size distribution.This provides determination of the quantitative ratio by particlediameter of composition comprising extended release particles. Sieveanalysis according to standard United States Pharmacopoeia methods(e.g., USP-23 NF 18), may be done such as by using a Meinzer II SieveShaker.

The granulated mixture can be blended with the polymer, filler andlubricant in a V-blender. The resultant mixture can be compressed intomonolithic, single-layer tablets using, for example, a Piccola Press ora Manesty® BB4 press, with the appropriate tooling.

Tablets may then be characterized with respect to disintegration anddissolution release profiles as well as tablet hardness, friability andcontent uniformity.

The dissolution and disintegration profiles for the tablets may bedetermined using a USP Dissolution Apparatus I, II or III tester or aUSP Disintegration tester, as is well known in the art. Tests may beperformed, for example, at about pH 1.2 (modified simulated gastricfluid, or mSFG), about pH 4.5 (the approximate pH of the stomach after ameal), about pH 6.8 or at about pH 7.5, at 37° C. Suitable aliquots ofthe release rate solutions are tested to determine the amount of drugreleased from the dosage form or pharmaceutical composition. Forexample, the drug can be assayed or injected into a chromatographicsystem to quantify the amounts of drug released during the testingintervals.

A tablet must disintegrate before it dissolves. A disintegration testermeasures the time it takes a tablet to break apart in solution. Thetester suspends tablets in a solution bath for visual monitoring of thedisintegration rate. Both the time to disintegration and thedisintegration consistency of all tablets are measured. Samples, 1 ml ateach time-point, may be taken, for example, without media replacement at0.125, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 7 and 8 hours. The resultingcumulative disintegration profiles are based upon a theoretical percentactive added to the formulation is determined.

Tablet hardness changes rapidly after compression as the tablet cools. Atablet that is too hard may not break up and dissolve into solutionbefore it passes through the body. In the case of the presentlydisclosed gastric retentive dosage forms, a tablet that is too hard maynot be able to imbibe fluid rapidly enough to prevent passage throughthe pylorus in a stomach in a fed mode. A tablet that is too soft maybreak apart, not handle well, and can create other defects inmanufacturing. A soft tablet may not package well or may not staytogether in transit.

After tablets are formed by compression, it is desired that the tabletshave a strength of at least 9-25 Kiloponds (Kp)/cm², preferably at leastabout 12-20 (Kp)/cm². A hardness tester is used to determine the loadrequired to diametrically break the tablets (crushing strength) into twoequal halves. The fracture force may be measured using a Venkel TabletHardness Tester, using standard USP protocols.

Friability is a well-known measure of a tablet's resistance to surfaceabrasion that measures weight loss in percentage after subjecting thetablets to a standardized agitation procedure. Friability properties areespecially relevant during any transport of the dosage form as anyfracturing of the final dosage form will result in a subject receivingless than the prescribed medication. Friability can be determined usinga Roche Friability Drum according to standard USP guidelines whichspecifies the number of samples, the total number of drum revolutionsand the drum rpm to be used. Friability values of from 0.8 to 1.0% areregarded as constituting the upper limit of acceptability.

The prepared tablets may be tested for content uniformity to determineif they meet the pharmaceutical requirement of <6% relative standarddeviation (RSD). Each tablet is placed in a solution of 1.0 N HCl andstirred at room temperature until all fragments have visibly dissolved.The solution containing the dissolved tablet is analyzed by HPLC.

In one aspect, a method of making a bilayer tablet comprising a gastricretentive extended-release layer and an immediate release layer isprovided.

V. Stability of Acamprosate Extended Release Formulations

Stability testing is the primary tool used to assess expiration datingand storage conditions for pharmaceutical products. Many protocols havebeen used for stability testing, but most in the industry are nowstandardizing on the recommendations of the International Conference onHarmonization (ICH). These guidelines were developed as a cooperativeeffort between regulatory agencies and industry officials from Europe,Japan, and the United States.

Stability testing includes long-term studies, where the product isstored at room temperature and humidity conditions, as well asaccelerated studies where the product is stored under conditions of highheat and humidity. Proper design, implementation, monitoring andevaluation of the studies are crucial for obtaining useful and accuratestability data. Stability studies are linked to the establishment andassurance of safety, quality and efficacy of the drug product from earlyphase development through the lifecycle of the drug product. Stabilitydata for the drug substance are used to determine optimal storage andpackaging conditions for bulk lots of the material. The stabilitystudies for the drug product are designed to determine the expirationdate (or shelf life). In order to assess stability, the appropriatephysical, chemical, biological and microbiological testing must beperformed. Usually this testing is a subset of the release testing.

Studies are designed to degrade the solid drug substance and appropriatesolutions, allowing the determination of the degradation profile. Thedrug substance is usually challenged under a variety of acceleratedenvironmental conditions to evaluate its intrinsic stability anddegradation profile.

HPLC is the predominant tool used to analyze the drug substance and theimpurities, particularly for small molecules. Frequently, the same HPLCmethod may be used for drug substance and drug product, althoughdifferent sample preparation methods would normally be required. Oftenthe assay and impurity testing can be performed using a single HPLCmethod. However, the assay and purity determinations may also beseparate methods. At least in the U.S., full validation of theanalytical method is not required until the end of Phase 2 clinicaltrials, but the establishment of specificity, linearity and limit ofquantification (for impurities) is considered at the earliest stages,since verification of stability hinges on a suitable method forseparating impurities from the active ingredient and at leastquantifying the impurities relative to the drug substance.

Stress studies at elevated temperature (e.g., 50° C., 60° C. and 70° C.)for several weeks may be performed to assess thermal stability. Providedthe degradation mechanism is the same at the different temperaturesused, kinetic or statistical models can be used to determine the rate ofdegradation at other temperatures (e.g., 25° C.). The solid stabilityshould also be performed in the presence and absence of water vapor toassess the dependence of stability on humidity.

Degradation studies should also be performed in solution. The solventused for the solution testing will depend on the solubility of the drugsubstance and should include water, if the drug substance iswater-soluble. Other solutions or solvent systems may be evaluateddepending on the anticipated formulation or the synthetic process. Aseries of buffered solutions in the pH range 2-9 are useful in assessingthe impact of solution pH on the degradation. Photostability should alsobe evaluated. A xenon light source can be used as a stress condition.Alternatively, one can use an accelerated version of either Options 1 or2 as described in the ICH guideline for determination of photostability.Oxidation of the drug substance under accelerated conditions (e.g.,hydrogen peroxide), may also be performed to establish oxidationproducts that could be formed and sensitivity to oxidative attack.

Early drug product stability studies are designed to help establish asuitable formulation for delivery of the drug substance. Compatibilitystudies of the drug substance with excipients should be performed toeliminate excipients that are not compatible with the drug substance.

VI. Methods of Treatment

In another aspect, the dosage form comprising acamprosate isadministered to a subject suffering from alcohol dependence, tinnitus,sleep apnea, Parkinson's disease, levodopa-induced dyskinesias inParkinson's disease, Alzheimer's disease, Huntington's disease,Amyotrophic lateral sclerosis, Cortical spreading depression, migraine,schizophrenia. Anxiety, tardive dyskinesia, spasticity, multiplesclerosis, various types of pain, or binge eating.

Generally, the frequency of administration of a particular dosage formis determined to provide the most effective results in an efficientmanner without overdosing and varies according to the followingcriteria: (1) the characteristics of the particular drug(s), includingboth its pharmacological characteristics and its physicalcharacteristics, such as solubility; (2) the characteristics of theswellable matrix, such as its permeability; and (3) the relative amountsof the drug and polymer. In most cases, the dosage form is prepared suchthat effective results are achieved with administration once every sixhours, once every eight hours, once every twelve hours, or once everytwenty-four hours. As previously discussed, due to the physicalconstraints placed on a tablet or capsule that is to be swallowed by apatient, most dosage forms can only support a limited amount of drugwithin a single dosage unit.

In one embodiment, the dosage form allows a dosing frequency of once aday (q.d.) or twice a day (b.i.d.) to provide a sustained concentrationof acamprosate in the subject's blood as compared to current immediaterelease products which require more frequent administration foreffective sustained therapy.

Within the context of the present disclosure, the gastric retentivedosage forms have the added advantage of improving patient compliancewith administration protocols because the drugs may be administered in aonce-daily or twice-daily dosing regimen, while still minimizing sideeffects associated with high doses and/or low concentrations of theactive agent (e.g., acamprosate) which result from commerciallyavailable forms of acamprosate.

For all modes of administration, the gastric retentive dosage formsdescribed herein are preferably administered in the fed mode, i.e., withor just after consumption of a small meal (see U.S. Publication No.2003/0104062, herein incorporated by reference).

In some aspects, the postprandial or fed mode can also be inducedpharmacologically, by the administration of pharmacological agents thathave an effect that is the same or similar to that of a meal. Thesefed-mode inducing agents may be administered separately or they may beincluded in the dosage form as an ingredient dispersed in the shell, inboth the shell and the core, or in an outer immediate release coating.Examples of pharmacological fed-mode inducing agents are disclosed inU.S. Pat. No. 7,405,238, entitled “Pharmacological Inducement of the FedMode for Enhanced Drug Administration to the Stomach,” the contents ofwhich are incorporated herein by reference.

All patents, patent applications, and publications mentioned herein arehereby incorporated by reference in their entireties. However, where apatent, patent application, or publication containing expressdefinitions is incorporated by reference, those express definitionsshould be understood to apply to the incorporated patent, patentapplication, or publication in which they are found, and not to thepresent disclosure or its claims.

EXAMPLES

The following examples are intended to illustrate the dosage forms,methods of manufacture, and methods of treatment, and are not intendedto limit the disclosure.

Example 1 Preparation of Gastric Retentive Dosage Forms for ExtendedRelease of Acamprosate

Two formulations of extended release acamprosate tablets, eachcontaining 666 mg acamprosate calcium and 17 wt % POLYOX 303 (averagemolecular weight of 7,000,000 Da) were initially produced. Formula I:66.6 wt % acamprosate calcium, 4 wt % polyvinylpovidone (PVP), 17 wt %POLYOX 303, 11.9 wt % Ceolus KG-1000 and 0.5 wt % magnesium stearate.Formula II: 66.6 wt % acamprosate calcium, 4 wt % polyvinylpyrrolidone(PVP), 17 wt % POLYOX 303, 11.9 wt % Eudragit RS PO, and 0.5 wt %magnesium stearate. These two formulas differed in the inclusion of theEudragit RS PO vs. Ceolus KG-1000 polymers. Ceolus KG-1000 is amicrocrystalline cellulose made with a very high aspect ratio. It may beused in small quantities to increase the compactability and hardness,and reduce friability of formulations, compared to other grades ofmicrocrystalline cellulose. Eudragit RS PO, and the related RL PO grade,are insoluble polymers which include a quaternary amine. Reasons forusing Eudragit RS PO include: to provide some swelling, to function asan insoluble excipient to slow the rate of hydration and further retardrelease of the drug, and to provide a cationic charge (via thequaternary amines on the polymer) to interact with the anionicacamprosate molecule to further retard release. Tablets weremanufactured using a dry blend process in which excipients were blendedin 2 ox glass jars. After each excipient was added, the blends werestirred by hand. The entire blend was then mixed for 2 minutes in thejar on a Turbula Mixer. Tablets having a total mass of 1000 mg were handmade on a Carver Auto C Press (Fred Carver, Inc., Indiana) andcompressed into tablets using a 0.4330″×0.7450″ Modified Oval die(Natoli Engineering, St. Charles, Mo.). The parameters for the operationof the Carver Auto C Press are as follows: 2000 lbs compression force, 0second dwell time (the setting on the Carver Press), and 100% pumpspeed.

Dissolution profiles were determined in a USP Dissolution Apparatus Itester in 900 ml modified simulated gastric fluid, pH 1.2, 40 mesh, 100rpm, at 37° C. Samples, 1 ml at each time-point, were taken withoutmedia replacement at 1, 2, 4, 6, 8 and 12 hours. The cumulativedissolution results, based upon a theoretical percent active added tothe formulation, are determined.

Release profiles for the Formula I and II tablets are presented below inTables 1 and 2 and are graphically represented in FIGS. 1 and 2.

TABLE 1 Lot# Formula I, 666 g Acamprosate Calcium Acamprosate CalciumCumulative Released (%) Hours 1 2 4 6 8 12 #1 27.4 44.2 66.4 80.1 89.396.9 #2 25.3 41.5 63.8 78.2 87.4 95.8 Average 26.4 42.8 65.1 79.2 88.496.3 StdDev 1.44 1.95 1.86 1.33 1.38 0.77 % CV 5.46 4.55 2.85 1.67 1.560.80

TABLE 2 Lot# Formula II, 666 g Acamprosate Calcium Acamprosate CalciumCumulative Released (%) Hours 1 2 4 6 8 12 #1 28.7 45.0 66.8 80.3 88.296.4 #2 27.4 44.4 67.4 81.6 90.3 97.6 Average 28.1 44.7 67.1 81.0 89.397.0 StdDev 0.89 0.46 0.43 0.86 1.54 0.83 % CV 3.18 1.02 0.64 1.06 1.720.86

The dissolution results show that both Formula I and Formula II tabletswere successful in providing a release of the acamprosate calcium over aperiod of at least 12 hours, with a release of about 90% between about 8and 12 hours.

Additional tablets were formulated to study the effects of POLYOX 1105(average molecular weight of 900,000) and Pearlitol 100 SD, a fineparticle of the soluble excipient mannitol. Pearlitol increases the rateof hydration to increase the rate of release and swelling by drawingdissolution media into the hydrating tablet faster than would aninsoluble excipient or POLYOX. Pearlitol also dissolves, leaving behindpores through which drug can freely diffuse.

Tablets having Formula III: 66.6 wt % acamprosate calcium, 4 wt % PVP,23.9 wt % POLYOX 303, 5 wt % Ceolus KG-1000 and 0.5 wt % Mg stearate,Formula IV: 66.6 wt % acamprosate calcium, 4 wt % PVP, 17 wt % POLYOX303, 6.9 wt % POLYOX 1105, 5 wt % Ceolus KG-1000 and 0.5 wt % Mgstearate, and Formula V: 66.6 wt % acamprosate calcium, 4 wt % PVP, 17wt % POLYOX 303, 11.9 wt % Pearlitol, and 0.5 wt % Mg stearate.Dissolution studies were carried out as described for Formulas I and IIand the data are presented below in Tables 3, 4, and 5.

TABLE 3 Formula III, 666 g Acamprosate Calcium Acamprosate CumulativeReleased (%) Hours 1 2 4 6 8 12 #1 24.0 39.3 61.5 75.8 86.0 95.4 #2 24.439.8 61.6 76.1 85.8 95.3 Average 24.2 39.6 61.5 76.0 85.9 95.3 Std Dev0.28 0.34 0.06 0.24 0.14 0.08 % CV 1.15 0.85 0.10 0.32 0.17 0.08

TABLE 4 Formula IV-TDRF, 666 g Acamprosate Calcium AcamprosateCumulative Released (%) Hours 1 2 4 6 8 12 #1 27.2 42.6 64.8 78.7 88.196.2 #2 27.7 43.2 64.9 79.4 88.6 96.7 Average 27.4 42.9 64.9 79.0 88.396.5 Std Dev 0.34 0.44 0.09 0.44 0.35 0.34 % CV 1.23 1.02 0.14 0.56 0.400.35

TABLE 5 Formula V-TDRF, 666 g Acamprosate Calcium Acamprosate CumulativeReleased (%) Hours 1 2 4 6 8 12 #1 28.9 45.5 68.0 81.5 90.5 97.5 #2 28.145.0 67.5 81.7 90.3 97.2 Average 28.5 45.2 67.8 81.6 90.4 97.3 Std Dev0.58 0.35 0.37 0.16 0.17 0.19 % CV 2.03 0.78 0.55 0.19 0.19 0.20

The data are shown schematically in FIG. 2. Again, the formulations weresuccessful in providing a release of the acamprosate over a period of atleast 12 hours with about 90% release occurring within 8-12 hours aftersubmersion in fluid.

Example 2 Swelling and Erosion Profiles of Gastric RetentiveExtended-Release Acamprosate Tablets

The swelling and erosion profiles of acamprosate dosage forms areassessed by monitoring weight change with time. Tablets are tested usingan Apparatus III (250 ml) USP Disintegration Tester in pH 4.5 acetatebuffer or in pH 7.5 phosphate buffer, at 37° C. Tablets are tested attime points between 0.25 and 8 hours. Each tablet is weighed, driedovernight at 50° C., then reweighed.

Example 3 Bioavailability Studies in Dogs

A study was performed to evaluate the pharmacokinetics of acamprosatedelivered from an IR formulation as compared to acamprosate deliveredvia simulated extended release (SER). Because acamprosate is absorbedonly in the upper small intestine and its absorption is known to be lessthan dose proportional, absorption is likely limited by permeabilitythrough the intestinal lining rather than dissolution from the oraldosage form. Accordingly, bioavailability may be improved by a gastricretentive extended-release formulation of acamprosate. Slow, continuousbathing of the upper small intestinal wall with a solution ofacamprosate may provide increased bioavailability as compared tobioavailability achieved upon the single bolus provided by an immediaterelease oral dosage form.

This study was conducted in 5 healthy beagle dogs weighing between 12-16kg to determine relative bioavailability of acamprosate whenadministered orally via the SER formulation as compared to the IRformulation (as a soft gel capsule). Following an overnight fast of atleast 12 hours, the dogs were fed 100 g canned dog food (Pedigree®Traditional ground Dinner with Chunky Chicken). The SER dosing wasdesigned to simulate a linear release with the square root of time overa period of about 8 hours. The dosing schedule of the SER acamprosatearm is presented below as Table 3.

TABLE 3 Time (h) Amount (mg) 0 81.2 0.5 33.6 1.0 25.8 1.5 21.8 2.0 19.22.5 17.3 3.0 15.9 3.5 14.8 4.0 13.9 4.5 13.2 5.0 12.5 5.5 12.0 6.0 11.56.5 11.1 7.0 10.7 7.5 10.3 Total Dose 324.8

Blood samples were drawn via venipuncture from the cephalic vein at 0.5h, 1.0 h, 2.0 h, 3.0 h, 4.0 h, 5.0 h, 6.0 h, 8.0 h, 10.0 h, 12.0 h and24 h post-dose. Samples were analyzed by LC-MS to determine acamprosateconcentration. AUC_(0-t) was calculated using non-compartmental analysis(WinNonlin). Cmax and tmax were obtained from inspection of individualplasma concentration-time data. Relative bioavailability of the SER tothe comparator (IR formulation) was calculated by dividing the AUC ofthe SER by the comparator's AUC. A paired t test on the In transformedAUC and Cmax was used to determine if there was a significantdifference. A p value of <0.05 was considered to be statisticallysignificant. A Wilcoxon signed-ranks test was used to determine if therewas a significant different between tmax values.

Results of the study are presented in Table 4 and presentedschematically in FIG. 3. As expected, a rapid rise in acamprosate plasmaconcentration was observed with the IR formulation, in which an averageCmax of 6976±1180 was obtained as compared to the average Cmax of4428±683 achieved with the SER dosing. The mean bioavailability of theSER formulation was about 154% of the IR formulation as calculated fromthe AUC values.

TABLE 4 AUC_(0-t) IR AUC_(0-t) SER R-BA C_(max) IR C_(max) SER Dog # (ng· h/mL) (ng · h/mL) (%) (ng/mL) (ng/mL) 1 31939 35185 110 7380 4620 231829 44221 1339 7150 5140 3 35345 39182 111 7550 4510 4 15929 32243 2024920 3290 5 21520 44786 208 7880 4580 Mean ± 27312 ± 8208 39123 ± 5498154 ± 48 6976 ± 1180 4428 ± 683 SD p value 0.0359 0.0013

Example 4 Erosion Studies with Gastric Retentive Extended-ReleaseAcamprosate Tablets in Beagle Dogs

This study is conducted in 4 or 5 healthy beagle dogs weighing between12-16 kg to determine the erosion time of different formulations ofgastric retentive extended-release acamprosate tablets. Following anovernight fast of at least 14 hours, the dogs are fed 100 g of canneddog food (Pedigree® Traditional ground Dinner with Chunky Chicken).Within 15 minutes of the dog consuming the meal they are administeredone of the acamprosate tablet formulations. Each dog receives eachformulation. There are at least 2 days between administrations of afirst and second formulation, and then a period of about 6 month elapsedbefore a third and fourth formulation is administered. Erosion of thegastric retentive extended-release tablets is assessed usingfluoroscopy. Each tablet contains two radio-opaque strings in the shapeof an “X”. Separation of the strings is considered to signify completeerosion of the tablets. Images are obtained every 30 minutes until thestrings separate. The recorded erosion time is the midpoint between thelast time the tablet was intact and when the strings are separated. Fromthe dog erosion study a prediction of delivery (erosion) time iscalculated based on a correlation developed between dog and human fromprevious erosional tablet studies.

Certain modifications and improvements will occur to those skilled inthe art upon a reading of the foregoing description. It should beunderstood that all such modifications and improvements have beendeleted herein for the sake of conciseness and readability but areproperly within the scope of the following claims.

The invention claimed is:
 1. A method for administering atherapeutically effective amount of a daily dose of about 300 mg toabout 2000 mg of acamprosate to a subject suffering from alcoholdependence, comprising administering to the subject acamprosate or apharmaceutically acceptable salt thereof dispersed in a gastric retaineddosage form to the subject in which a fed mode has been induced andwherein the dosage form comprises a single polymer matrix comprising atleast one swellable hydrophilic polymer that swells in a dimensionallyunrestrained manner by imbibing water to increase its size to promotegastric retention of the dosage form in the stomach of the subject,wherein upon contact with aqueous fluid, at least about 80% of theacamprosate in the extended release portion of the dosage form isreleased by the dosage form over a period of at least about 5 hours, andwherein upon administration to the subject, the gastric retained dosageform provides a mean AUC of plasma acamprosate which is at least 50%greater than the mean AUC of plasma acamprosate provided by an immediaterelease (IR) dosage form or pharmaceutically acceptable salt thereofequal to or more than the dose of acamprosate in the gastric retaineddosage form.
 2. The method of claim 1, wherein the gastric retentivedosage form provides a mean C_(max) of plasma acamprosate which is about60% to 70% of the mean C_(max) of plasma acamprosate provided by an IRdosage form which contains a dose of acamprosate or pharmaceuticallyacceptable salt thereof equal to or less than the dose of acamprosate inthe gastric retentive dosage form.
 3. The method of claim 1, wherein thegastric retained dosage form provides a T_(max) which is about 3 hoursto 8 hours greater than the T_(max) provided by an IR dosage form whichcontains a dose of acamprosate or pharmaceutically acceptable saltthereof equal to or less than the dose of acamprosate in the gastricretentive dosage form.
 4. The method of claim 1, wherein said dose isadministered with a meal.
 5. The method of claim 1, wherein the dailydose is administered as a single dose per a 24 hour period.
 6. Themethod of claim 1, wherein the daily dose is administered as two dosesper a 24 hour period.